19-nor neuroactive steroids and methods of use thereof

ABSTRACT

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): 
     
       
         
         
             
             
         
       
     
     and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, status epilepticus.

CLAIM OF PRIORITY

This application is a continuation of Ser. No. 15/273,125 filed Sep. 22,2016, which is a continuation of Ser. No. 14/785,162 filed Apr. 17,2014, which is a national stage application under U.S.C. § 371 ofInternational Application No. PCT/CN2014/075600, filed Apr. 17, 2014,published as International Publication No. WO2014/169836A1 on Oct. 23,2014, which claims priority to International Application No.PCT/CN2013/074319, filed on Apr. 17, 2013, the contents of each of whichis incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Brain excitability is defined as the level of arousal of an animal, acontinuum that ranges from coma to convulsions, and is regulated byvarious neurotransmitters. In general, neurotransmitters are responsiblefor regulating the conductance of ions across neuronal membranes. Atrest, the neuronal membrane possesses a potential (or membrane voltage)of approximately −70 mV, the cell interior being negative with respectto the cell exterior. The potential (voltage) is the result of ion (K⁺,Na⁺, Cl⁻, organic anions) balance across the neuronal semipermeablemembrane. Neurotransmitters are stored in presynaptic vesicles and arereleased under the influence of neuronal action potentials. Whenreleased into the synaptic cleft, an excitatory chemical transmittersuch as acetylcholine will cause membrane depolarization (change ofpotential from −70 mV to −50 mV). This effect is mediated bypostsynaptic nicotinic receptors which are stimulated by acetylcholineto increase membrane permeability to Na⁺ ions. The reduced membranepotential stimulates neuronal excitability in the form of a postsynapticaction potential.

In the case of the GABA receptor complex (GRC), the effect on brainexcitability is mediated by GABA, a neurotransmitter. GABA has aprofound influence on overall brain excitability because up to 40% ofthe neurons in the brain utilize GABA as a neurotransmitter. GABAregulates the excitability of individual neurons by regulating theconductance of chloride ions across the neuronal membrane. GABAinteracts with its recognition site on the GRC to facilitate the flow ofchloride ions down an electrochemical gradient of the GRC into the cell.An intracellular increase in the levels of this anion causeshyperpolarization of the transmembrane potential, rendering the neuronless susceptible to excitatory inputs (i.e., reduced neuronexcitability). In other words, the higher the chloride ion concentrationin the neuron, the lower the brain excitability (the level of arousal).

It is well-documented that the GRC is responsible for the mediation ofanxiety, seizure activity, and sedation. Thus, GABA and drugs that actlike GABA or facilitate the effects of GABA (e.g., the therapeuticallyuseful barbiturates and benzodiazepines (BZs), such as Valium®) producetheir therapeutically useful effects by interacting with specificregulatory sites on the GRC. Accumulated evidence has now indicated thatin addition to the benzodiazepine and barbiturate binding site, the GRCcontains a distinct site for neuroactive steroids (Lan, N. C. et al.,Neurochem. Res. 16:347-356 (1991)).

Neuroactive steroids can occur endogenously. The most potent endogenousneuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and3α-21-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonalsteroids progesterone and deoxycorticosterone, respectively. The abilityof these steroid metabolites to alter brain excitability was recognizedin 1986 (Majewska, M. D. et al., Science 232:1004-1007 (1986); Harrison,N. L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

The ovarian hormone progesterone and its metabolites have beendemonstrated to have profound effects on brain excitability (Backstrom,T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130:19-24 (1985); Pfaff,D. W and McEwen, B. S., Science 219:808-814 (1983); Gyermek et al., JMed Chem. 11: 117 (1968); Lambert, J. et al., Trends Pharmacol. Sci.8:224-227 (1987)). The levels of progesterone and its metabolites varywith the phases of the menstrual cycle. It has been well documented thatthe levels of progesterone and its metabolites decrease prior to theonset of menses. The monthly recurrence of certain physical symptomsprior to the onset of menses has also been well documented. Thesesymptoms, which have become associated with premenstrual syndrome (PMS),include stress, anxiety, and migraine headaches (Dalton, K.,Premenstrual Syndrome and Progesterone Therapy, 2nd edition, ChicagoYearbook, Chicago (1984)). Subjects with PMS have a monthly recurrenceof symptoms that are present in premenses and absent in postmenses.

In a similar fashion, a reduction in progesterone has also beentemporally correlated with an increase in seizure frequency in femaleepileptics, i.e., catamenial epilepsy (Laidlaw, J., Lancet, 1235-1237(1956)). A more direct correlation has been observed with a reduction inprogesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg.Psych. 49:47-51 (1986)). In addition, for subjects with primarygeneralized petit mal epilepsy, the temporal incidence of seizures hasbeen correlated with the incidence of the symptoms of premenstrualsyndrome (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20(1983)). The steroid deoxycorticosterone has been found to be effectivein treating subjects with epileptic spells correlated with theirmenstrual cycles (Aird, R. B. and Gordan, G., J. Amer. Med. Soc.145:715-719 (1951)).

A syndrome also related to low progesterone levels is postnataldepression (PND). Immediately after birth, progesterone levels decreasedramatically leading to the onset of PND. The symptoms of PND range frommild depression to psychosis requiring hospitalization. PND is alsoassociated with severe anxiety and irritability. PND-associateddepression is not amenable to treatment by classic antidepressants, andwomen experiencing PND show an increased incidence of PMS (Dalton, K.,Premenstrual Syndrome and Progesterone Therapy, 2nd edition, ChicagoYearbook, Chicago (1984)).

Collectively, these observations imply a crucial role for progesteroneand deoxycorticosterone and more specifically their metabolites in thehomeostatic regulation of brain excitability, which is manifested as anincrease in seizure activity or symptoms associated with catamenialepilepsy, PMS, and PND. The correlation between reduced levels ofprogesterone and the symptoms associated with PMS, PND, and catamenialepilepsy (Backstrom, T. et al., J Psychosom. Obstet. Gynaecol. 2:8-20(1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2ndedition, Chicago Yearbook, Chicago (1984)) has prompted the use ofprogesterone in their treatment (Mattson et al., “Medroxyprogesteronetherapy of catamenial epilepsy,” in Advances in Epileptology: XVthEpilepsy International Symposium, Raven Press, New York (1984), pp.279-282, and Dalton, K., Premenstrual Syndrome and Progesterone Therapy,2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone isnot consistently effective in the treatment of the aforementionedsyndromes. For example, no dose-response relationship exists forprogesterone in the treatment of PMS (Maddocks et al., Obstet. Gynecol.154:573-581 (1986); Dennerstein et al., Brit. Med J 290:16-17 (1986)).

New and improved neuroactive steroids are needed that act as modulatingagents for brain excitability, as well as agents for the prevention andtreatment of CNS-related diseases. The compounds, compositions, andmethods described herein are directed toward this end.

SUMMARY OF THE INVENTION

The present invention is based, in part, on the desire to provide novel19-nor (i.e., C19 desmethyl) compounds, e.g., related to progesterone,deoxycorticosterone, and their metabolites, with good potency,pharmacokinetic (PK) properties, oral bioavailability, formulatability,stability, safety, clearance and/or metabolism. One key feature of thecompounds as described herein is disubstitution at the C3 position(e.g., with one substituent being a 3α hydroxy moiety. The inventorsenvision disubstitution at C-3 will eliminate the potential foroxidation of the hydroxy moiety to the ketone, prevent furthermetabolism, and reduce the potential for secondary elimination pathways,such as glucuronidation. The inventors further envision the overalleffect of C3 disubstitution should be of improving the overall PKparameters and reducing potential toxicities and side effects, which mayallow, in certain embodiments, administration orally and/or chronically.Another key feature of the compounds as described herein is the presenceof a hydrogen at the C19 position (“19-nor”) rather than a methyl group.The inventors envision 19-nor compounds, as compared to their C19-methylcounterparts, will have improved physical properties, such as improvedsolubility. The inventors envision further enhancement of solubility,for example, when the AB ring system is in the cis configuration.

Thus, in one aspect, provided herein are compounds of Formula (I):

and pharmaceutically acceptable salts thereof;wherein:

-   -   represents a single or double bond;    -   R¹ is substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl;    -   R² is hydrogen, halogen, substituted or unsubstituted C₁₋₆        alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted or        unsubstituted C₂₋₆ alkynyl, or substituted or unsubstituted C₃₋₆        carbocyclyl, or —OR^(A2), wherein R^(A2) is hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl;    -   R^(3a) is hydrogen or —OR^(A3), wherein R^(A3) is hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl, and        R^(3b) is hydrogen; or R^(3a) and R^(3b) are joined to form an        oxo (═O) group;    -   each instance of R^(4a) and R^(4b) is independently hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, or halogen, provided if        the        between C5 and C6 is a single bond, then the hydrogen at C5 is        in the alpha or beta configuration; and provided if the        between C5 and C6 is a double bond, R^(4b) is absent;    -   A is one of the following formulae:

-   -   each instance of R⁵ is, independently, halogen, —NO₂, —CN,        —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),        —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,        —N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂,        —N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA),        —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂, or —N(R^(GA))S(═O)₂R^(GA);        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, substituted or unsubstituted C₃₋₄ carbocylyl,        substituted or unsubstituted 3- to 4-membered heterocylyl, or        optionally two R^(GA) are taken with the intervening atoms to        form a substituted or unsubstituted 3- to 4-membered carbocyclic        or heterocyclic ring;    -   each instance of R^(AN) is independently hydrogen, substituted        or unsubstituted C₁₋₆ alkyl, —C(═O)R^(GA), —C(═O)OR^(GA),        —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA), —S(O)₂OR^(GA),        —S(═O)₂N(R^(GA))₂, —S(O)R^(GA), e.g., —S(═O)R^(GA),        —S(═O)OR^(GA), —S(═O)N(R^(GA))₂, or a nitrogen protecting group;    -   each instance of R^(GA) is independently hydrogen, substituted        or unsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆        alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted        or unsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted        3- to 6-membered heterocylyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, an oxygen protecting        group when attached to oxygen, a nitrogen protecting group when        attached to nitrogen, or two R^(GA) groups are taken with the        intervening atoms to form a substituted or unsubstituted        carbocyclic or heterocyclic ring;    -   p is 1 or 2; and    -   e is 0, 1, 2, 3, 4, or 5;    -   provided that when A is (A-2), (A-3), or (A-5), e is 1, 2, 3, or        4.

In another aspect of the invention, provided herein are compounds ofFormula (I):

and pharmaceutically acceptable salts thereof;wherein:

-   -   represents a single or double bond;    -   R¹ is substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl;    -   R² is hydrogen, halogen, substituted or unsubstituted C₁₋₆        alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted or        unsubstituted C₂₋₆ alkynyl, or substituted or unsubstituted C₃₋₆        carbocyclyl, or —OR^(A2), wherein R^(A2) is hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl;    -   R^(3a) is hydrogen or —OR^(A3), wherein R^(A3) is hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl, and        R^(3b) is hydrogen; or R^(3a) and R^(3b) are joined to form an        oxo (═O) group;    -   each instance of R^(4a) and R^(4b) is independently hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, or halogen, provided if        the        between C5 and C6 is a single bond, then the hydrogen at C5 is        in the alpha or beta configuration; and provided if the        between C5 and C6 is a double bond, R^(4b) is absent;    -   A is

-   -   each instance of R⁵ is, independently, halogen, —NO₂, —CN,        —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),        —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,        —N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂,        —N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA),        —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂, or —N(R^(GA))S(═O)₂R^(GA);        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, substituted or unsubstituted C₃₋₄ carbocylyl,        substituted or unsubstituted 3- to 4-membered heterocylyl, or        optionally two R^(GA) are taken with the intervening atoms to        form a substituted or unsubstituted 3- to 4-membered carbocyclic        or heterocyclic ring;    -   each instance of R^(AN) is independently hydrogen, substituted        or unsubstituted C₁₋₆ alkyl, —C(═O)R^(GA), —C(═O)OR^(GA),        —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA), —S(═O)₂OR^(GA),        —S(═O)₂N(R^(GA))₂, —S(O)R^(GA), e.g., —S(═O)R^(GA),        —S(═O)OR^(GA), —S(═O)N(R^(GA))₂, or a nitrogen protecting group;    -   each instance of R^(GA) is independently hydrogen, substituted        or unsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆        alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted        or unsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted        3- to 6-membered heterocylyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, an oxygen protecting        group when attached to oxygen, a nitrogen protecting group when        attached to nitrogen, or two R^(GA) groups are taken with the        intervening atoms to form a substituted or unsubstituted        carbocyclic or heterocyclic ring;    -   p is 1 or 2; and    -   e is 0, 1, 2, 3, 4, or 5;    -   provided that when e is 0, at least one of R², R^(3a), R^(4a),        and R^(4b) is not hydrogen.

Compounds of Formula (I), sub-genera thereof, and pharmaceuticallyacceptable salts thereof are collectively referred to herein as“compounds of the present invention.” In another aspect, provided is apharmaceutical composition comprising a compound of the presentinvention and a pharmaceutically acceptable excipient. In certainembodiments, the compound of the present invention is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the compound of the present invention is provided in atherapeutically effective amount. In certain embodiments, the compoundof the present invention is provided in a prophylactically effectiveamount.

Compounds of the present invention as described herein, act, in certainembodiments, as GABA modulators, e.g., effecting the GABA_(A) receptorin either a positive or negative manner. As modulators of theexcitability of the central nervous system (CNS), as mediated by theirability to modulate GABA_(A) receptor, such compounds are expected tohave CNS-activity.

Thus, in another aspect, provided are methods of treating a CNS-relateddisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of the present invention. Incertain embodiments, the CNS-related disorder is selected from the groupconsisting of a sleep disorder, a mood disorder, a schizophreniaspectrum disorder, a convulsive disorder, a disorder of memory and/orcognition, a movement disorder, a personality disorder, autism spectrumdisorder, pain, traumatic brain injury, a vascular disease, a substanceabuse disorder and/or withdrawal syndrome, and tinnitus. In certainembodiments, the compound is administered orally, subcutaneously,intravenously, or intramuscularly. In certain embodiments, the compoundis administered chronically.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing Detailed Description,Examples, and Claims.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention. When describing the invention,which may include compounds, pharmaceutical compositions containing suchcompounds and methods of using such compounds and compositions, thefollowing terms, if present, have the following meanings unlessotherwise indicated. It should also be understood that when describedherein any of the moieties defined forth below may be substituted with avariety of substituents, and that the respective definitions areintended to include such substituted moieties within their scope as setout below. Unless otherwise stated, the term “substituted” is to bedefined as set out below. It should be further understood that the terms“groups” and “radicals” can be considered interchangeable when usedherein. The articles “a” and “an” may be used herein to refer to one orto more than one (i.e. at least one) of the grammatical objects of thearticle. By way of example “an analogue” means one analogue or more thanone analogue.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms(“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbonatoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl grouphas 1 to 6 carbon atoms (“C₁₋₆ alkyl”, also referred to herein as “loweralkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groupsinclude methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C), and n-hexyl (C₆). Additional examples of alkyl groupsinclude n-heptyl (C₇), n-octyl (C₈) and the like. Unless otherwisespecified, each instance of an alkyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkyl”) orsubstituted (a “substituted alkyl”) with one or more substituents; e.g.,for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkyl group is unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group issubstituted C₁₋₁₀ alkyl. Common alkyl abbreviations include Me (—CH₃),Et (—CH₂CH₃), iPr (—CH(CH₃)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃),or i-Bu (—CH₂CH(CH₃)₂).

As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to adivalent radical of an alkyl, alkenyl, and alkynyl group, respectively.When a range or number of carbons is provided for a particular“alkylene,” “alkenylene,” and “alkynylene” group, it is understood thatthe range or number refers to the range or number of carbons in thelinear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene”groups may be substituted or unsubstituted with one or more substituentsas described herein.

“Alkylene” refers to an alkyl group wherein two hydrogens are removed toprovide a divalent radical, and which may be substituted orunsubstituted. Unsubstituted alkylene groups include, but are notlimited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—),hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—), and the like. Exemplary substitutedalkylene groups, e.g., substituted with one or more alkyl (methyl)groups, include but are not limited to, substituted methylene(—CH(CH₃)—, (—C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene(—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—), and the like.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkenylene” refers to an alkenyl group wherein two hydrogens areremoved to provide a divalent radical, and which may be substituted orunsubstituted. Exemplary unsubstituted divalent alkenylene groupsinclude, but are not limited to, ethenylene (—CH═CH—) and propenylene(e.g., —CH═CHCH₂—, —CH₂—CH═CH—). Exemplary substituted alkenylenegroups, e.g., substituted with one or more alkyl (methyl) groups,include but are not limited to, substituted ethylene (—C(CH₃)═CH—,—CH═C(CH₃)—), substituted propylene (e.g., —C(CH₃)═CHCH₂—,—CH═C(CH₃)CH₂—, —CH═CHCH(CH₃)—, —CH═CHC(CH₃)₂—, —CH(CH₃)—CH═CH—,—C(CH₃)₂—CH═CH—, —CH₂—C(CH₃)═CH—, —CH₂—CH═C(CH₃)—), and the like.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents; e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Alkynylene” refers to a linear alkynyl group wherein two hydrogens areremoved to provide a divalent radical, and which may be substituted orunsubstituted. Exemplary divalent alkynylene groups include, but are notlimited to, substituted or unsubstituted ethynylene, substituted orunsubstituted propynylene, and the like.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4)heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus)within the parent chain, wherein the one or more heteroatoms is insertedbetween adjacent carbon atoms within the parent carbon chain and/or oneor more heteroatoms is inserted between a carbon atom and the parentmolecule, i.e., between the point of attachment. In certain embodiments,a heteroalkyl group refers to a saturated group having from 1 to 10carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₁₀ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₉ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 8carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₈ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 7carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₇ alkyl”). In someembodiments, a heteroalkyl group is a group having 1 to 6 carbon atomsand 1, 2, or 3 heteroatoms (“heteroC₁₋₆ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₄ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1heteroatom (“heteroC₁₋₃ alkyl”). In some embodiments, a heteroalkylgroup is a saturated group having 1 to 2 carbon atoms and 1 heteroatom(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC₂₋₆ alkyl”).Unless otherwise specified, each instance of a heteroalkyl group isindependently unsubstituted (an “unsubstituted heteroalkyl”) orsubstituted (a “substituted heteroalkyl”) with one or more substituents.In certain embodiments, the heteroalkyl group is an unsubstitutedheteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkyl group is asubstituted heteroC₁₋₁₀ alkyl.

The term “heteroalkenyl,” as used herein, refers to an alkenyl group, asdefined herein, which further comprises one or more (e.g., 1, 2, 3, or4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon,phosphorus) wherein the one or more heteroatoms is inserted betweenadjacent carbon atoms within the parent carbon chain and/or one or moreheteroatoms is inserted between a carbon atom and the parent molecule,i.e., between the point of attachment. In certain embodiments, aheteroalkenyl group refers to a group having from 2 to 10 carbon atoms,at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC₂₋₁₀alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbonatoms at least one double bond, and 1, 2, 3, or 4 heteroatoms(“heteroC₂₋₉ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4heteroatoms (“heteroC₂₋₈ alkenyl”). In some embodiments, a heteroalkenylgroup has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or4 heteroatoms (“heteroC₂₋₇ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1, 2, or 3 heteroatoms (“heteroC₂₋₆ alkenyl”). In some embodiments,a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond,and 1 or 2 heteroatoms (“heteroC₂₋₅ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 4 carbon atoms, at least one double bond,and 1 or 2 heteroatoms (“heteroC₂₋₄ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 3 carbon atoms, at least one double bond,and 1 heteroatom (“heteroC₂₋₃ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or 2 heteroatoms (“heteroC₂₋₆ alkenyl”). Unless otherwisespecified, each instance of a heteroalkenyl group is independentlyunsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certainembodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀alkenyl. In certain embodiments, the heteroalkenyl group is asubstituted heteroC₂₋₁₀ alkenyl.

The term “heteroalkynyl,” as used herein, refers to an alkynyl group, asdefined herein, which further comprises one or more (e.g., 1, 2, 3, or4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon,phosphorus) wherein the one or more heteroatoms is inserted betweenadjacent carbon atoms within the parent carbon chain and/or one or moreheteroatoms is inserted between a carbon atom and the parent molecule,i.e., between the point of attachment. In certain embodiments, aheteroalkynyl group refers to a group having from 2 to 10 carbon atoms,at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC₂₋₁₀alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbonatoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms(“heteroC₂₋₉ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4heteroatoms (“heteroC₂₋₈ alkynyl”). In some embodiments, a heteroalkynylgroup has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or4 heteroatoms (“heteroC₂₋₇ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1, 2, or 3 heteroatoms (“heteroC₂₋₆ alkynyl”). In some embodiments,a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms (“heteroC₂₋₅ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms (“heteroC₂₋₄ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond,and 1 heteroatom (“heteroC₂₋₃ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms (“heteroC₂₋₆ alkynyl”). Unless otherwisespecified, each instance of a heteroalkynyl group is independentlyunsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a“substituted heteroalkynyl”) with one or more substituents. In certainembodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀alkynyl. In certain embodiments, the heteroalkynyl group is asubstituted heteroC₂₋₁₀ alkynyl.

As used herein, “alkylene,” “alkenylene,” “alkynylene,”“heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” refer to adivalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl,heteroalkenyl, and heteroalkynyl group respectively. When a range ornumber of carbons is provided for a particular “alkylene,” “alkenylene,”“alkynylene,” “heteroalkylene,” “heteroalkenylene,” or“heteroalkynylene,” group, it is understood that the range or numberrefers to the range or number of carbons in the linear carbon divalentchain. “Alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,”“heteroalkenylene,” and “heteroalkynylene” groups may be substituted orunsubstituted with one or more substituents as described herein.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl. Unless otherwise specified, eachinstance of an aryl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted aryl”) or substituted (a “substitutedaryl”) with one or more substituents. In certain embodiments, the arylgroup is unsubstituted C₆₋₁₄ aryl. In certain embodiments, the arylgroup is substituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁-C₈ alkyl, C₁-C₈ haloalkyl, cyano, hydroxy,C₁-C₈ alkoxy, and amino.

Examples of representative substituted aryls include the following

wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ andR⁵⁷ is each independently selected from C₁-C₈ alkyl, C₁-C₈ haloalkyl,4-10 membered heterocyclyl, alkanoyl, C₁-C₈ alkoxy, heteroaryloxy,alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹ NR⁵⁸SO₂R⁵⁹,COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl,SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶ and R⁵⁷ may be joinedto form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,optionally containing one or more heteroatoms selected from the group N,O, or S. R⁶⁰ and R⁶¹ are independently hydrogen, C₁-C₈ alkyl, C₁-C₄haloalkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,substituted C₆-C₁₀ aryl, 5-10 membered heteroaryl, or substituted 5-10membered heteroaryl.

Other representative aryl groups having a fused heterocyclyl groupinclude the following:

wherein each W is selected from C(R⁶⁶)₂, NR⁶⁶, O, and S; and each Y isselected from carbonyl, NR⁶⁶, O and S; and R⁶⁶ is independentlyhydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl,C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Fused aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl or heteroaryl ring or with a carbocyclyl orheterocyclyl ring.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refersto an optionally substituted alkyl group substituted by an optionallysubstituted aryl group.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Y is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein,and refers to an optionally substituted alkyl group substituted by anoptionally substituted heteroaryl group.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

Particular examples of heterocyclyl groups are shown in the followingillustrative examples:

wherein each W is selected from CR⁶⁷, C(R⁶⁷)₂, NR⁶⁷, O, and S; and eachY is selected from NR⁶⁷, O, and S; and R⁶⁷ is independently hydrogen,C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,5-10 membered heteroaryl. These heterocyclyl rings may be optionallysubstituted with one or more groups selected from the group consistingof acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoylor amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl,aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto,nitro, thiol, —S-alkyl, —S-aryl, —S(O)-alkyl, —S(O)-aryl, —S(O)₂-alkyl,and —S(O)₂-aryl. Substituting groups include carbonyl or thiocarbonylwhich provide, for example, lactam and urea derivatives.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g.,heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like havingfrom 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, asdefined herein. “Alkanoyl” is an acyl group wherein R²⁰ is a group otherthan hydrogen. Representative acyl groups include, but are not limitedto, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), —C(O)—C₁-C₈ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein tis an integer from 0 to 4. In certain embodiments, R²¹ is C₁-C₈ alkyl,substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Acylamino” refers to a radical —NR²²C(O)R²³, where each instance of R²²and R²³ is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, as defined herein, or R²² is anamino protecting group. Exemplary “acylamino” groups include, but arenot limited to, formylamino, acetylamino, cyclohexylcarbonylamino,cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.Particular exemplary “acylamino” groups are —NR²⁴C(O)—C₁-C₈ alkyl,—NR²⁴C(O)—(CH₂)_(t)(C₆-C₁₀ aryl), —NR²⁴C(O)—(CH₂)_(t)(5-10 memberedheteroaryl), —NR²⁴C(O)—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR²⁴C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, and each R²⁴ independently represents H or C₁-C₈ alkyl. Incertain embodiments, R²⁵ is H, C₁-C₈ alkyl, substituted with halo orhydroxy; C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which issubstituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy; and R²⁶ is H, C₁-C₈ alkyl,substituted with halo or hydroxy; C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxyl; provided at least one of R²⁵ and R²⁶ is other than H.

“Acyloxy” refers to a radical —OC(O)R²⁷, where R²⁷ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, as defined herein. Representative examples include, but arenot limited to, formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certainembodiments, R²⁸ is C₁-C₈ alkyl, substituted with halo or hydroxy;C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl, arylalkyl,5-10 membered heteroaryl or heteroarylalkyl, each of which issubstituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆-C₁₀ aryl, aryloxy, carboxyl,cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Exemplary‘substituted alkoxy’ groups include, but are not limited to,—O—(CH₂)_(t)(C₆-C₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or an amino protecting group, wherein at leastone of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ isindependently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈alkynyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocyclyl, or C₃-C₁₀ cycloalkyl; or C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₈ alkenyl, substituted with halo or hydroxy; C₃-C₈alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃-C₁₀ cycloalkyl), or—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integer between0 and 8, each of which is substituted by unsubstituted C₁-C₄ alkyl,halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy; or both R³⁸ groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to,—NR³⁹—C₁-C₈ alkyl, —NR³⁹—(CH₂)_(t)(C₆-C₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10membered heteroaryl), —NR³⁹—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR³⁹—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, for instance 1 or 2, each R³⁹ independently represents H orC₁-C₈ alkyl; and any alkyl groups present, may themselves be substitutedby halo, substituted or unsubstituted amino, or hydroxy; and any aryl,heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselvesbe substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. For the avoidance of doubtthe term ‘substituted amino’ includes the groups alkylamino, substitutedalkylamino, alkylarylamino, substituted alkylarylamino, arylamino,substituted arylamino, dialkylamino, and substituted dialkylamino asdefined below. Substituted amino encompasses both monosubstituted aminoand disubstituted amino groups.

“Azido” refers to the radical —N₃.

“Carbamoyl” or “amido” refers to the radical —C(O)NH₂.

“Substituted carbamoyl” or “substituted amido” refers to the radical—C(O)N(R⁶²)₂ wherein each R⁶² is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, or an amino protectinggroup, wherein at least one of R⁶² is not a hydrogen. In certainembodiments, R⁶² is selected from H, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl,4-10 membered heterocyclyl, C₆-C₁₀ aryl, aralkyl, 5-10 memberedheteroaryl, and heteroaralkyl; or C₁-C₈ alkyl substituted with halo orhydroxy; or C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which issubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy; provided that at least oneR⁶² is other than H.

Exemplary “substituted carbamoyl” groups include, but are not limitedto, —C(O) NR⁶⁴—C₁-C₈ alkyl, —C(O)NR⁶⁴—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)N⁶⁴—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)NR⁶⁴—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)NR⁶⁴—(CH₂)_(t)(4-10 membered heterocyclyl),wherein t is an integer from 0 to 4, each R⁶⁴ independently represents Hor C₁-C₈ alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclylgroups present, may themselves be substituted by unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group issubstituted with a cycloalkyl group. Typical cycloalkylalkyl groupsinclude, but are not limited to, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

“Heterocyclylalkyl” refers to an alkyl radical in which the alkyl groupis substituted with a heterocyclyl group. Typical heterocyclylalkylgroups include, but are not limited to, pyrrolidinylmethyl,piperidinylmethyl, piperazinylmethyl, morpholinylmethyl,pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl,and the like.

“Cycloalkenyl” refers to substituted or unsubstituted carbocyclyl grouphaving from 3 to 10 carbon atoms and having a single cyclic ring ormultiple condensed rings, including fused and bridged ring systems andhaving at least one and particularly from 1 to 2 sites of olefinicunsaturation. Such cycloalkenyl groups include, by way of example,single ring structures such as cyclohexenyl, cyclopentenyl,cyclopropenyl, and the like.

“Fused cycloalkenyl” refers to a cycloalkenyl having two of its ringcarbon atoms in common with a second aliphatic or aromatic ring andhaving its olefinic unsaturation located to impart aromaticity to thecycloalkenyl ring.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—.

“Ethynyl” refers to —(C≡C)—.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

“Thioketo” refers to the group ═S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. For purposes of this invention,heteroatoms such as nitrogen may have hydrogen substituents and/or anysuitable substituent as described herein which satisfy the valencies ofthe heteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(O)R^(aa), e.g., —S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(cc))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

-   -   or two geminal hydrogens on a carbon atom are replaced with the        group ═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa),        ═NNR^(bb)C(═O)OR^(aa), ═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or        ═NOR^(cc);    -   each instance of R^(aa) is, independently, selected from C₁₋₁₀        alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀        carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14        membered heteroaryl, or two R^(aa) groups are joined to form a        3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,        wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,        aryl, and heteroaryl is independently substituted with 0, 1, 2,        3, 4, or 5 R^(dd) groups;    -   each instance of R^(bb) is, independently, selected from        hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),        —C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa),        —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),        —SOR^(cc), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),        —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,        —P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered        heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two        R^(bb) groups are joined to form a 3-14 membered heterocyclyl or        5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,        alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is        independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)        groups;    -   each instance of R^(cc) is, independently, selected from        hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄        aryl, and 5-14 membered heteroaryl, or two R^(cc) groups are        joined to form a 3-14 membered heterocyclyl or 5-14 membered        heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,        carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently        substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;    -   each instance of R^(dd) is, independently, selected from        halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee),        —ON(R^(ff))₂, —N(R^(ff))₂, —N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff),        —SH, —SR^(ee), —SSR^(ee), —C(═O)R^(ee), —CO₂H, —CO₂R^(ee),        —OC(═O)R^(ee), —OCO₂R^(ee), —C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂,        —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂,        —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee), OC(═NR^(ff))OR^(ee),        —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,        —NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee),        —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),        —S(O)R^(cc), e.g., —S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃,        —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee),        —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,        —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl,        alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and        heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5        R^(gg) groups, or two geminal R^(dd) substituents can be joined        to form ═O or ═S;    -   each instance of R^(ee) is, independently, selected from C₁₋₆        alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, and 3-10        membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,        carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently        substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; each        instance of R^(ff) is, independently, selected from hydrogen,        C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10        membered heteroaryl, or two R^(ff) groups are joined to form a        3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,        wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,        aryl, and heteroaryl is independently substituted with 0, 1, 2,        3, 4, or 5 R^(gg) groups; and    -   each instance of R^(gg) is, independently, halogen, —CN, —NO₂,        —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆        alkyl)₂, —N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆        alkyl)⁺X⁻, —NH₃ ⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆        alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆        alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆        alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl),        —NHC(═O)(C₁ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆        alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl),        —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),        —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆        alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆        alkyl), —OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂,        —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl),        —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl,        —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆        alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆ alkyl),        —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),        —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆        alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered        heterocyclyl, 5-10 membered heteroaryl; or two geminal R^(gg)        substituents can be joined to form ═O or ═S; wherein X⁻ is a        counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, SO₄ ⁻²sulfonateions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions(e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate,tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substituents include, but are not limitedto, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of the present invention include those derivedfrom suitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁺(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-50 depict representative ¹H NMR spectra of exemplary compoundsdescribed herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

As described herein, the present invention provides 3,3-disubstituted19-nor neuroactive steroids of Formula (I):

and pharmaceutically acceptable salts thereof;wherein:

-   -   represents a single or double bond;    -   R¹ is substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl;    -   R² is hydrogen, halogen, substituted or unsubstituted C₁₋₆        alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted or        unsubstituted C₂₋₆ alkynyl, or substituted or unsubstituted C₃₋₆        carbocyclyl, or —OR^(A2), wherein R^(A2) is hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl;    -   R^(3a) is hydrogen or —OR^(A3), wherein R^(A3) is hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl, and        R^(3b) is hydrogen; or R^(3a) and R^(3b) are joined to form an        oxo (═O) group;    -   each instance of R^(4a) and R^(4b) is independently hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, or halogen, provided if        the        between C5 and C6 is a single bond, then the hydrogen at C5 is        in the alpha or beta configuration; and provided if the        between C5 and C6 is a double bond, R^(4b) is absent;    -   A is one of the following formulae:

-   -   each instance of R⁵ is, independently, halogen, —NO₂, —CN,        —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),        —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,        —N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂,        —N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA),        —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂, or —N(R^(GA))S(═O)₂R^(GA);        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, substituted or unsubstituted C₃₋₄ carbocylyl,        substituted or unsubstituted 3- to 4-membered heterocylyl, or        optionally two R^(GA) are taken with the intervening atoms to        form a substituted or unsubstituted 3- to 4-membered carbocyclic        or heterocyclic ring;    -   each instance of R^(AN) is independently hydrogen, substituted        or unsubstituted C₁₋₆ alkyl, —C(═O)R^(GA), —C(═O)OR^(GA),        —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA), —S(═O)₂OR^(GA),        —S(═O)₂N(R^(GA))₂, —S(O)R^(GA), e.g., —S(═O)R^(GA),        —S(═O)OR^(GA), —S(═O)N(R^(GA))₂, or a nitrogen protecting group;    -   each instance of R^(GA) is independently hydrogen, substituted        or unsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆        alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted        or unsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted        3- to 6-membered heterocylyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, an oxygen protecting        group when attached to oxygen, a nitrogen protecting group when        attached to nitrogen, or two R^(GA) groups are taken with the        intervening atoms to form a substituted or unsubstituted        carbocyclic or heterocyclic ring;    -   p is 1 or 2; and    -   e is 0, 1, 2, 3, 4, or 5.

In certain embodiments, A is (A-2), (A-3), or (A-5), and e is 1, 2, 3,4, or 5.

In certain embodiments, A is

e is 0; and at least one of R², R^(3a), R^(4a), and R^(4b) is nothydrogen.

It is understood, based on the aforementioned description, thatcompounds of Formula (I) encompass 3,3-disubstituted 19-nor neuroactivesteroids wherein the A/B ring system of the compound is cis (as providedin Formula (I-A), wherein the A/B ring system of the compound is trans(as provided in Formula (I-B), and wherein the B ring of the compoundcomprises a C₅-C₆ double bond (as provided in Formula (I-C)):

and pharmaceutically acceptable salts thereof.

Group R¹

As generally defined herein, R¹ is substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, or substituted or unsubstituted C₃₋₆carbocyclyl.

In certain embodiments, R¹ is substituted or unsubstituted C₁₋₆ alkyl,e.g., substituted or unsubstituted C₁₋₂alkyl, substituted orunsubstituted C₂₋₃alkyl, substituted or unsubstituted C₃₋₄alkyl,substituted or unsubstituted C₄₋₅alkyl, or substituted or unsubstitutedC₅₋₆alkyl. Exemplary R¹ C₁₋₆alkyl groups include, but are not limitedto, substituted or unsubstituted methyl (C₁), ethyl (C₂), n-propyl (C₃),isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl(C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl (C₅),3-methyl-2-butanyl (C₅), tertiary amyl (C₅), n-hexyl (C₆), C₁₋₆ alkylsubstituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups(e.g., —CF₃, —CH₂F, —CHF₂, difluoroethyl, and2,2,2-trifluoro-1,1-dimethyl-ethyl), C₁₋₆ alkyl substituted with 1, 2,3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups (e.g., —CH₂Cl, —CHCl₂),and C₁₋₆ alkyl substituted with alkoxy groups (e.g., —CH₂OCH₃ and—CH₂OCH₂CH₃). In certain embodiments, R¹ is substituted C₁₋₆ alkyl,e.g., R¹ is haloalkyl, alkoxyalkyl, or aminoalkyl. In certainembodiments, R¹ is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl,difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl,2,2,2-trifluoro-1,1-dimethyl-ethyl, methoxymethyl, methoxyethyl, orethoxymethyl.

In certain embodiments, R¹ is unsubstituted C₁₋₃ alkyl, e.g., R¹ is—CH₃, —CH₂CH₃, or —CH₂CH₂CH₃.

In certain embodiments, R¹ is C₁₋₆ alkyl substituted with one or morefluorine atoms; e.g., R¹ is —CH₂F, —CHF₂, or —CF₃.

In certain embodiments, R¹ is C₁₋₆ alkyl substituted with one or more—OR^(A1) groups, wherein R^(A1) is hydrogen or substituted orunsubstituted alkyl. In certain embodiments, R¹ is —CH₂OR^(A1), e.g.,wherein R^(A1) is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃, e.g., toprovide a group R¹ of formula —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, or—CH₂OCH₂CH₂CH₃.

In certain embodiments, R¹ is substituted or unsubstituted C₂₋₆ alkenyl,e.g., substituted or unsubstituted C₂₋₃alkenyl, substituted orunsubstituted C₃₋₄alkenyl, substituted or unsubstituted C₄₋₅alkenyl, orsubstituted or unsubstituted C₅₋₆alkenyl. In certain embodiments, R¹ isethenyl (C₂), propenyl (C₃), or butenyl (C₄), unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. Incertain embodiments, R¹ is ethenyl, propenyl, or butenyl, unsubstitutedor substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy. Incertain embodiments, R¹ is ethenyl.

In certain embodiments, R¹ is substituted or unsubstituted C₂₋₆ alkynyl,e.g., substituted or unsubstituted C₂₋₃alkynyl, substituted orunsubstituted C₃₋₄alkynyl, substituted or unsubstituted C₄₋₅alkynyl, orsubstituted or unsubstituted C₅₋₆alkynyl. In certain embodiments, R¹ isethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl,halo, haloalkyl (e.g., CF₃), alkoxyalkyl, cycloalkyl (e.g., cyclopropylor cyclobutyl), or hydroxyl. In certain embodiments, R¹ is selected fromthe group consisting of trifluoroethynyl, cyclopropylethynyl,cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. Incertain embodiments, R¹ is ethynyl (C₂), propynyl (C₃), or butynyl (C₄),unsubstituted or substituted with one or more substituents selected fromthe group consisting of substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl,and substituted or unsubstituted heterocyclyl. In certain embodiments,R¹ is ethynyl (C₂), propynyl (C₃), or butynyl (C₄) substituted withsubstituted phenyl. In certain embodiments, the phenyl substituent isfurther substituted with one or more substituents selected from thegroup consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino oramido. In certain embodiments, R¹ is ethynyl (C₂), propynyl (C₃), orbutynyl (C₄) substituted with substituted or unsubstituted pyrrolyl,imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl,1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.

In certain embodiments, R¹ is ethynyl, propynyl, or butynyl,unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl,or hydroxyl. In certain embodiments, R¹ is ethynyl or propynyl,substituted with substituted or unsubstituted aryl. In certainembodiments, R¹ is ethynyl or propynyl, substituted with phenylunsubstituted or substituted with halo, alkyl, alkoxy, haloalkyl,trihaloalkyl, or acyl. In certain embodiments, R¹ is ethynyl orpropynyl, substituted with substituted or unsubstituted carbocyclyl. Incertain embodiments, R^(3a) is ethynyl or propynyl, substituted withsubstituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In certain embodiments, R¹ is ethynyl or propynyl,substituted with substituted or unsubstituted heteroaryl. In certainembodiments, R¹ is ethynyl or propynyl, substituted with substituted orunsubstituted pyridinyl, or pyrimidinyl. In certain embodiments, R¹ isethynyl or propynyl, substituted with substituted or unsubstitutedpyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl,1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl.In certain embodiments, R¹ is ethynyl or propynyl, substituted withsubstituted or unsubstituted heterocyclyl. In certain embodiments, R¹ isethynyl or propynyl, substituted with substituted or unsubstitutedpyrrolidinyl, piperidinyl, piperazinyl, or mopholinyl. In certainembodiments, R¹ is propynyl or butynyl, substituted with hydroxyl oralkoxy. In certain embodiments, R¹ is propynyl or butynyl, substitutedwith methoxy or ethoxy. In certain embodiments, R¹ is ethynyl orpropynyl, substituted with chloro. In certain embodiments, R¹ is ethynylor propynyl, substituted with trifluoromethyl.

In certain embodiments, R¹ is substituted or unsubstituted C₃₋₆carbocyclyl, e.g., substituted or unsubstituted C₃₋₄carbocyclyl,substituted or unsubstituted C₄₋₅ carbocyclyl, or substituted orunsubstituted C₅₋₆ carbocyclyl. In certain embodiments, R¹ issubstituted or unsubstituted cyclopropyl or substituted or unsubstitutedcyclobutyl.

Groups

, R², R^(3a), R^(3b), R^(4a), and R^(4b)

As generally defined herein, R² is hydrogen, halogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, or substituted orunsubstituted C₃₋₆ carbocyclyl, or —OR^(A2), wherein R^(A2) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, or substitutedor unsubstituted C₃₋₆ carbocyclyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R² ishalogen, e.g., fluoro, chloro, bromo, or iodo. In certain embodiments,R² is fluoro or chloro. In certain embodiments, R² is substituted orunsubstituted C₁₋₆alkyl, e.g., substituted or unsubstituted C₁₋₂alkyl,substituted or unsubstituted C₂₋₃alkyl, substituted or unsubstitutedC₃₋₄alkyl, substituted or unsubstituted C₄₋₅alkyl, or substituted orunsubstituted C₅₋₆alkyl. In certain embodiments, R² is substituted orunsubstituted C₂₋₆ alkenyl, In certain embodiments, R² is substituted orunsubstituted C₂₋₆ alkynyl, e.g., substituted or unsubstitutedC₂₋₃alkynyl, substituted or unsubstituted C₃₋₄alkynyl, substituted orunsubstituted C₄₋₅alkynyl, or substituted or unsubstituted C₅₋₆alkynyl.In certain embodiments, R² is substituted or unsubstituted C₃₋₆carbocyclyl, e.g., substituted or unsubstituted C₃₋₄carbocyclyl,substituted or unsubstituted C₄₋₅ carbocyclyl, or substituted orunsubstituted C₅₋₆ carbocyclyl. In certain embodiments, R² issubstituted or unsubstituted cyclopropyl or substituted or unsubstitutedcyclobutyl. In certain embodiments, R² is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, orsubstituted or unsubstituted cyclopropyl. In certain embodiments, R² is—OR^(A2). In certain embodiments, R^(A2) is hydrogen. In certainembodiments, R^(A2) is substituted or unsubstituted alkyl, e.g.,substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstitutedC₁₋₂alkyl, substituted or unsubstituted C₂₋₃alkyl, substituted orunsubstituted C₃₋₄alkyl, substituted or unsubstituted C₄₋₅alkyl, orsubstituted or unsubstituted C₅₋₆alkyl. In certain embodiments, R^(A2)is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃, i.e., to provide a group R²of formula —OH, —OCH₃, —OCH₂CH₃, or —OCH₂CH₂CH₃. In certain embodiments,R² is a non-hydrogen substituent in the alpha configuration. In certainembodiments, R² is a non-hydrogen substituent in the beta configuration.

As generally defined herein, R^(3a) is hydrogen or —OR^(A3), whereinR^(A3) is hydrogen or substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, or substituted or unsubstituted C₃₋₆ carbocylyl, andR^(3b) is hydrogen; or R^(3a) and R^(3b) are joined to form an oxo (═O)group.

In certain embodiments, both R^(3a) and R^(3b) are both hydrogen.

In certain embodiments, R^(3a) and R^(3b) are joined to form an oxo (═O)group.

In certain embodiments, R^(3a) is —OR^(A3) and R^(3b) is hydrogen. Incertain embodiments, wherein R^(3a) is —OR^(A3), R^(3a) is in the alphaor beta configuration. In certain embodiments, wherein R^(3a) is—OR^(A3), R^(3a) is in the alpha configuration. In certain embodiments,wherein R^(3a) is —OR^(A3), R^(3a) is in the beta configuration. Incertain embodiments, R^(A3) is hydrogen. In certain embodiments, R^(A3)is substituted or unsubstituted C₁₋₆ alkyl, e.g., substituted orunsubstituted C₁₋₂alkyl, substituted or unsubstituted C₂₋₃alkyl,substituted or unsubstituted C₃₋₄alkyl, substituted or unsubstitutedC₄₋₅alkyl, or substituted or unsubstituted C₅₋₆alkyl. In certainembodiments, R^(A3) is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃, i.e., toprovide a group R^(3a) of formula —OH, —OCH₃, —OCH₂CH₃, or —OCH₂CH₂CH₃.

As generally defined herein, each instance of R^(4a) and R^(4b) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl, orhalogen, provided if the

between C5 and C6 are single bonds, then the hydrogen at C5 and R^(4a)are each independently provided in the alpha or beta configuration, andR^(4b) is absent.

In certain embodiments,

is a single bond, at least one of R^(4a) and R^(4b) is hydrogen. Incertain embodiments,

is a single bond, at least one of R^(4a) and R^(4b) is substituted orunsubstituted C₁₋₆ alkyl, e.g., substituted or unsubstituted C₁₋₂alkyl,substituted or unsubstituted C₂₋₃alkyl, substituted or unsubstitutedC₃₋₄alkyl, substituted or unsubstituted C₄₋₅alkyl, or substituted orunsubstituted C₅₋₆alkyl. In certain embodiments,

is a single bond, at least one of R^(4a) and R^(4b) is C₁ alkyl, e.g.,—CH₃ or —CF₃. In certain embodiments,

is a single bond, at least one of R^(4a) and R^(4b) is halogen, e.g.,fluoro.

In certain embodiments,

is a single bond, and both of R^(4a) and R^(4b) are hydrogen. In certainembodiments,

is a single bond, and both of R^(4a) and R^(4b) are independentlysubstituted or unsubstituted C₁₋₆ alkyl, e.g., substituted orunsubstituted C₁₋₂alkyl, substituted or unsubstituted C₂₋₃alkyl,substituted or unsubstituted C₃₋₄alkyl, substituted or unsubstitutedC₄₋₅alkyl, or substituted or unsubstituted C₅₋₆alkyl. In certainembodiments,

is a single bond, and both of R^(4a) and R^(4b) are independently C₁alkyl, e.g., —CH₃ or —CF₃. In certain embodiments,

is a single bond, and both of R^(4a) and R^(4b) are halogen, e.g.,fluoro.

In certain embodiments, wherein

represents a single bond, R^(4a) is a non-hydrogen substituent in thealpha configuration. In certain embodiments, wherein

represents a single bond, R^(4a) is a non-hydrogen substituent in thebeta configuration.

In certain embodiments,

is a double bond, and R^(4a) is hydrogen. In certain embodiments,

is a double bond, and R^(4a) is substituted or unsubstituted C₁₋₆ alkyl,e.g., substituted or unsubstituted C₁₋₂alkyl, substituted orunsubstituted C₂₋₃alkyl, substituted or unsubstituted C₃₋₄alkyl,substituted or unsubstituted C₄₋₅alkyl, or substituted or unsubstitutedC₅₋₆alkyl. In certain embodiments,

is a double bond, and R^(4a) is C₁ alkyl, e.g., —CH₃ or —CF₃. In certainembodiments,

is a double bond, and R^(4a) is halogen, e.g., fluoro.

Groups A

As generally defined herein, A is one of the following formulae:

wherein:

-   -   each instance of R⁵ is, independently, halogen, —NO₂, —CN,        —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),        —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,        —N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂,        —N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA),        —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂, or —N(R^(GA))S(═O)₂R^(GA);        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, substituted or unsubstituted C₃₋₄ carbocylyl,        substituted or unsubstituted 3- to 4-membered heterocylyl, or        optionally two R^(GA) are taken with the intervening atoms to        form a substituted or unsubstituted 3- to 4-membered carbocyclic        or heterocyclic ring;    -   each instance of R^(AN) is independently hydrogen, substituted        or unsubstituted C₁₋₆ alkyl, —C(═O)R^(GA), —C(═O)OR^(GA),        —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA), —S(═O)₂OR^(GA),        —S(═O)₂N(R^(GA))₂, —S(O)R^(GA), e.g., —S(═O)R^(GA),        —S(═O)OR^(GA), —S(═O)N(R^(GA))₂, or a nitrogen protecting group;    -   each instance of R^(GA) is independently hydrogen, substituted        or unsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆        alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted        or unsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted        3- to 6-membered heterocylyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, an oxygen protecting        group when attached to oxygen, a nitrogen protecting group when        attached to nitrogen, or two R^(GA) groups are taken with the        intervening atoms to form a substituted or unsubstituted        carbocyclic or heterocyclic ring;    -   p is 1 or 2; and    -   e is 0, 1, 2, 3, 4, or 5.

In certain embodiments, A is of Formula (A-1) (A-1)

In certain embodiments, A is of Formula (A-2)

In certain embodiments, A is of Formula (A-3)

In certain embodiments, A is of Formula (A-4)

In certain embodiments, A is of Formula (A-5)

It is to be understood that each instance of R⁵ can adopt either alphaor beta configuration (e.g., R or S configuration).

In certain embodiments, A is one of the following formulae

As generally defined herein, p is 1 or 2. In certain embodiments, pis 1. In certain embodiments, p is 2.

As generally defined herein, e is 0, 1, 2, 3, 4, or 5. In certainembodiments, e is 0. In certain embodiments, e is 1. In certainembodiments, e is 2. In certain embodiments, e is 3. In certainembodiments, e is 4. In certain embodiments, e is 5.

As generally defined herein, each instance of R⁵ is, independently,halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),—OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂, or—N(R^(GA))S(═O)₂R^(GA); substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₄ carbocylyl, substitutedor unsubstituted 3- to 4-membered heterocylyl, or optionally two R⁵ aretaken with the intervening atoms to form a substituted or unsubstituted3- to 4-membered carbocyclic or heterocyclic ring. In some embodiments,R⁵ is halogen. In certain embodiments, R⁵ is F. In certain embodiments,R⁵ is Cl. In certain embodiments, R⁵ is Br. In certain embodiments, R⁵is I. In certain embodiments, R⁵ is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, R⁵ is substituted C₁₋₆ alkyl. In certainembodiments, R⁵ is —CF₃. In certain embodiments, R⁵ is —CHF₂. In certainembodiments, R⁵ is —CH₂F. In certain embodiments, R⁵ is unsubstitutedC₁₋₆ alkyl. In certain embodiments, R⁵ is methyl, ethyl, propyl, butyl,pentyl, or hexyl. In certain embodiments, R⁵ is isopropyl, isobutyl, orisoamyl. In certain embodiments, R⁵ is isobutyl. In certain embodiments,R⁵ is tert-butyl. In some embodiments, R⁵ is —CN. In some embodiments,R⁵ is —NO₂. In some embodiments, R⁵ is substituted or unsubstitutedcarbocyclyl. In some embodiments, R⁵ is substituted or unsubstitutedphenyl. In some embodiments, R⁵ is substituted or unsubstitutedheterocyclyl. In some embodiments, R⁵ is substituted or unsubstitutedheteroaryl. In certain embodiments, R is —OR^(GA), —N(R^(GA))₂,—C(═O)R^(GA), —C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA),—C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂,—N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, or —N(R^(GA))S(═O)₂R^(GA). In certain embodiments, R⁵is —C(═O)R^(GA), wherein R^(GA) is methyl, ethyl, or propyl. In certainembodiments, R⁵ is —NHR^(GA). In certain embodiments, R⁵ is —NHR^(GA),wherein R^(GA) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R⁵ is —NHR^(GA), wherein R^(GA) is unsubstituted C₁₋₆alkyl. In certain embodiments, R⁵ is —NHR^(GA), wherein R^(GA) ismethyl, ethyl, or propyl. In certain embodiment, R is —NHR^(GA), whereinR^(B) is substituted C₁₋₆ alkyl. In certain embodiments, R is—N(R^(GA))₂, wherein each R^(GA) is independently substituted orunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(GA) is —N(R^(B))₂,wherein each R^(GA) is independently unsubstituted C₁₋₆ alkyl. Incertain embodiments, R⁵ is —N(R^(GA))₂, wherein each R^(GA) isindependently selected from the group consisting of methyl, ethyl,isopropyl, isobutyl, isoamyl, and benzyl. In some embodiments, R⁵ is—N(R^(GA))₂, wherein each R^(GA) is the same. In some embodiments, R is—N(R^(GA))₂, wherein each R^(GA) is different. In certain embodiments, Ris —NH₂. In certain embodiments, R is —OR^(GA). In certain embodiments,R is —OH. In certain embodiments, R is —OR^(GA), wherein R^(GA) issubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R⁵ is—OR^(GA), wherein R^(GA) is unsubstituted C₁₋₆ alkyl. In certainembodiments, R⁵ is —O-propyl, —O-isopropyl, —O-isobutyl, or —O-isoamyl.In certain embodiments, R is —OR^(GA) wherein R^(GA) is substituted C₁₋₆alkyl. In certain embodiments, R⁵ is —OR^(GA), wherein R^(GA) issubstituted or unsubstituted heterocyclyl. In certain embodiments, R⁵ is—OR^(GA), wherein R^(GA) is substituted or unsubstituted aryl. Incertain embodiments, R⁵ is —O-phenyl. In certain embodiments, R⁵ is—S(═O)₂R^(GA), wherein R^(GA) is methyl, ethyl, or propyl. In certainembodiments, two R⁵ are taken with the intervening atoms to form asubstituted or unsubstituted 3- to 4-membered carbocyclic orheterocyclic ring. In certain embodiments, two R⁵ are taken with theintervening atoms to form a substituted or unsubstituted 3-memberedcarbocyclic ring. In certain embodiments, two R⁵ are taken with theintervening atoms to form a substituted or unsubstituted 3-memberedheterocyclic ring. In certain embodiments, two R⁵ are taken with theintervening atoms to form a substituted or unsubstituted 4-memberedcarbocyclic ring. In certain embodiments, two R⁵ are taken with theintervening atoms to form a substituted or unsubstituted 4-memberedheterocyclic ring.

As generally defined herein, each instance of R^(GA) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocylyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, an oxygen protectinggroup when attached to oxygen, a nitrogen protecting group when attachedto nitrogen, or two R^(GA) groups are taken with the intervening atomsto form a substituted or unsubstituted heterocylyl or heteroaryl ring.In some embodiments, R^(GA) is hydrogen. In certain embodiments, R^(GA)is substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, or substitutedor unsubstituted C₃₋₆ carbocyclyl. In certain embodiments, R^(GA) issubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(GA)is unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(GA) is methyl,ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, R^(GA)is isopropyl, isobutyl, or isoamyl. In certain embodiments, R^(GA) isisobutyl. In certain embodiments, R⁵ is tert-butyl. In certainembodiments, R^(GA) is substituted or unsubstituted heterocyclyl. Incertain embodiments, R^(GA) is substituted or unsubstituted aryl. Incertain embodiments, R^(GA) is substituted or unsubstituted phenyl. Incertain embodiments, R^(GA) is a nitrogen protecting group. In certainembodiments, R^(GA) is an oxygen protecting group.

In certain embodiments, e is 0. In certain embodiments, e is 1 and R⁵ issubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, e is 1and R⁵ is methyl, ethyl, or propyl. In certain embodiments, e is 2 andat least one instance of R⁵ is substituted or unsubstituted C₁₋₆ alkyl.In certain embodiments, e is 2 and at least one instance of R⁵ ismethyl, ethyl, or propyl. In certain embodiments, e is 3 and at leastone instance of R⁵ is substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, e is 3 and at least one instance of R⁵ is methyl,ethyl, or propyl. In certain embodiments, e is 4 and at least oneinstance of R⁵ is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, e is 4 and at least one instance of R⁵ is methyl, ethyl, orpropyl. In certain embodiments, e is 5 and at least one instance of R⁵is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, e is5 and at least one instance of R⁵ is methyl, ethyl, or propyl. Incertain embodiments, e is 1 and R⁵ is OR^(GA), wherein R^(GA) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, e is 1 and R⁵ is OH. In certain embodiments, e is 2and at least one instance of R⁵ is OR^(GA), wherein R^(GA) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, e is 2 and at least one instance of R⁵ is OH. Incertain embodiments, e is 3 and at least one instance of R is OR^(GA),wherein R^(GA) is independently hydrogen, substituted or unsubstitutedC₁₋₆ alkyl. In certain embodiments, e is 3 and at least one instance ofR⁵ is OH. In certain embodiments, e is 4 and at least one instance of R⁵is OR^(GA) wherein R^(GA) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl. In certain embodiments, e is 4 and at leastone instance of R⁵ is OH. In certain embodiments, e is 5 and at leastone instance of R⁵ is OR^(GA), wherein R^(GA) is independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, e is 5and at least one instance of R⁵ is OH.

As generally defined herein, each instance of R^(AN) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl, —C(═O)R^(GA),—C(═O)OR^(GA), —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA), —S(═O)₂OR^(GA),—S(═O)₂N(R^(GA))₂, —S(O)R^(GA), e.g., —S(═O)R^(GA), —S(═O)OR^(GA),—S(═O)N(R^(GA))₂, or a nitrogen protecting group. In some embodiments,R^(AN) is hydrogen. In some embodiments, R^(AN) is substituted orunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(AN) is methyl. Incertain embodiments, R^(AN) is ethyl. In certain embodiments, R^(AN) ispropyl. In certain embodiments, R^(AN) is —C(═O)R^(GA). In certainembodiments, R^(A) is —C(═O)R^(GA), wherein R^(GA) is independentlysubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A)is —C(═O)R^(GA), wherein R^(GA) is unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(A) is —C(═O)R^(GA), wherein R^(GA) is substituted C₁₋₆alkyl. In certain embodiments, R^(A) is —C(═O)R^(GA), wherein R^(GA) ismethyl, ethyl, or propyl. In certain embodiments, R^(AN) is—C(═O)OR^(GA). In certain embodiments, R^(AN) is —C(═O)OR^(GA), whereinR^(GA) is independently substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(AN) is —C(═O)OR^(GA) wherein R^(GA) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(AN) is—C(═O)OR^(GA), wherein R^(GA) is substituted C₁₋₆ alkyl. In certainembodiments, R^(AN) is —C(═O)OR^(GA), wherein R^(GA) is methyl, ethyl,or propyl. In certain embodiments, R^(AN) is —C(═O)N(R^(GA))₂. Incertain embodiments, R^(AN) is —C(═O)N(R^(GA))₂, wherein each instanceof R^(GA) is independently hydrogen or substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, R^(A) is —C(═O)N(R^(GA))₂, wherein twoR^(GA) are the same. In certain embodiments, R^(AN) is —C(═O)N(R^(GA))₂,wherein two R^(GA) are different. In certain embodiments, R^(A) is—C(═O)NHR^(GA), wherein R^(GA) is substituted C₁₋₆ alkyl. In certainembodiments, R^(AN) is —C(═O)NHR^(GA), wherein R^(GA) is unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(AN) is —C(═O)NHR^(GA), whereinR^(GA) is methyl, ethyl, or propyl. In certain embodiments, R^(AN) is—C(═O)N(R^(GA))₂, wherein each instance of R^(GA) is substituted orunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(AN) is—C(═O)N(R^(GA))₂, wherein each instance of R^(GA) is unsubstituted C₁₋₆alkyl. In certain embodiments, R^(A) is —C(═O)N(R^(GA))₂, wherein eachinstance of R^(GA) is methyl, ethyl, or propyl. In certain embodiments,R^(A) is —S(═O)₂R^(GA). In certain embodiments, R^(A) is —S(═O)₂R^(GA),wherein R^(GA) is independently substituted or unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(A) is —S(═O)₂R^(GA), wherein R^(GA) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(AN) is—S(═O)₂R^(GA), wherein R^(GA) is substituted C₁₋₆ alkyl. In certainembodiments, R^(AN) is —S(═O)₂R^(GA), wherein R^(GA) is methyl, ethyl,or propyl. In certain embodiments, R^(AN) is nitrogen protecting group.In certain embodiments, R^(AN) is Bn, BOC, Cbz, Fmoc, trifluoroacetyl,triphenylmethyl, or Ts.

In certain embodiments, the compound of Formula (I) is of Formula (II)

or a pharmaceutically acceptable salt thereof.

In some aspects of these embodiments, e is 0, 1, 2, 3, 4, or 5.

In certain embodiments, the compound of Formula (I) is of Formula (III)

or a pharmaceutically acceptable salt thereof.

In some aspects of these embodiments, e is 1, 2, 3, 4, or 5. In certainembodiments, e is 1. In certain embodiments, e is 2. In certainembodiments, e is 3. In certain embodiments, e is 4. In certainembodiments, e is 5.

In some aspects of these embodiments, the compound is one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof, wherein R^(5X), R^(5Y),R^(5X1), R^(5X2), R^(5Y1), and R^(5Y2) are each independently hydrogen,halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, or substituted orunsubstituted C₁₋₆ alkyl.

In certain embodiments, the compound of Formula (I) is of Formula (IV)

or a pharmaceutically acceptable salt thereof.

In some aspects of these embodiments, e is 1, 2, 3, 4, or 5. In certainembodiments, e is 1. In certain embodiments, e is 2. In certainembodiments, e is 3. In certain embodiments, e is 4. In certainembodiments, e is 5.

The compound of Formula (I) is of one of the following formulae:

or a pharmaceutically acceptable salt thereof, wherein R^(5X), R^(5Y),R^(5X1), R^(5X2), R^(5Y1), and R^(5Y1) are each independently hydrogen,halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, or substituted orunsubstituted C₁₋₆ alkyl.

In certain embodiments, the compound of Formula (I) is of Formula (V)

or a pharmaceutically acceptable salt thereof.

In some aspects of these embodiments, e is 0, 1, 2, 3, 4, or 5.

In certain embodiments, the compound of Formula (I) is of Formula (VI)

or a pharmaceutically acceptable salt thereof.

In some aspects of these embodiments, e is 1, 2, 3, 4, or 5. In certainembodiments, e is 1. In certain embodiments, e is 2. In certainembodiments, e is 3. In certain embodiments, e is 4. In certainembodiments, e is 5.

In some aspects of these embodiments, e is 0. In some aspects of theseembodiments, at least one of R², R^(3a), R^(4a), and R^(4b) is nothydrogen.

As used herein, R^(5X) is independently hydrogen, halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, or substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(5X) is hydrogen. In certain embodiments, R^(5X)is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments,R^(5X) is unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(5X) ismethyl, ethyl, or propyl. In certain embodiments, R^(5X) is halogen. Incertain embodiments, R^(5X) is NO₂. In certain embodiments, R^(5X) isCN. In certain embodiments, R^(5X) is —OR^(GA), wherein R^(GA) ishydrogen or substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(5X) is —OH. In certain embodiments, R^(5X) is —NHR^(GA),wherein R^(GA) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, ora nitrogen protecting group. In certain embodiments, R^(5X) is —NH₂. Incertain embodiments, R^(5X) is —N(R^(GA))₂, wherein R^(GA) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.

As used herein, R^(5X1) is independently hydrogen, halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, or substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(5X1) is hydrogen. In certain embodiments,R^(5X1) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(5X1) is unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(5X1) is methyl, ethyl, or propyl. In certainembodiments, R^(5X1) is halogen. In certain embodiments, R^(5X1) is NO₂.In certain embodiments, R^(5X1) is CN. In certain embodiments, R^(5X1)is —OR^(GA), wherein R^(GA) is hydrogen or substituted or unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(5X1) is —OH. In certainembodiments, R^(5X1) is —NHR^(GA), wherein R^(GA) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.In certain embodiments, R^(5X1) is —NH₂. In certain embodiments, R^(5X1)is —N(R^(GA))₂, wherein R^(GA) is hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, or a nitrogen protecting group.

As used herein, R^(5X2) is independently hydrogen, halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, or substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(5X2) is hydrogen. In certain embodiments,R^(5X2) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(5X2) is unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(5X2) is methyl, ethyl, or propyl. In certainembodiments, R^(5X2) is halogen. In certain embodiments, R^(5X2) is NO₂.In certain embodiments, R^(5X2) is CN. In certain embodiments, R^(5X2)is —OR^(GA), wherein R^(GA) is hydrogen or substituted or unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(5X2) is —OH. In certainembodiments, R^(5X2) is —NHR^(GA), wherein R^(GA) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.In certain embodiments, R^(5X2) is —NH₂. In certain embodiments, R^(5X2)is —N(R^(GA))₂, wherein R^(GA) is hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, or a nitrogen protecting group.

As used herein, R^(5Y) is independently hydrogen, halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, or substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(5Y) is hydrogen. In certain embodiments, R^(5Y)is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments,R^(5Y) is unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(5Y) ismethyl, ethyl, or propyl. In certain embodiments, R^(5Y) is halogen. Incertain embodiments, R^(5Y) is NO₂. In certain embodiments, R^(5Y) isCN. In certain embodiments, R is —OR^(GA), wherein R^(GA) is hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R is—OH. In certain embodiments, R is —NHR^(GA), wherein R^(GA) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.In certain embodiments, R^(5Y) is —NH₂. In certain embodiments, R^(5Y)is —N(R^(GA))₂, wherein R^(GA) is hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, or a nitrogen protecting group.

As used herein, R^(5Y1) is independently hydrogen, halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, or substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(5Y1) is hydrogen. In certain embodiments,R^(5Y1) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(5Y1) is unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(5Y1) is methyl, ethyl, or propyl. In certainembodiments, R^(5Y1) is halogen. In certain embodiments, R^(5Y1) is NO₂.In certain embodiments, R^(5Y1) is CN. In certain embodiments, R^(5Y1)is —OR^(GA), wherein R^(GA) is hydrogen or substituted or unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(5Y1) is —OH. In certainembodiments, R^(5Y1) is —NHR^(GA), wherein R^(GA) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.In certain embodiments, R^(5Y1) is —NH₂. In certain embodiments, R^(5Y1)is —N(R^(GA))₂, wherein R^(GA) is hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, or a nitrogen protecting group.

As used herein, R^(5Y2) is independently hydrogen, halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, or substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(5Y2) is hydrogen. In certain embodiments,R^(5Y2) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(5Y2) is unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(5Y2) is methyl, ethyl, or propyl. In certainembodiments, R^(5Y2) is halogen. In certain embodiments, R^(5Y2) is NO₂.In certain embodiments, R^(5Y2) is CN. In certain embodiments, R^(5Y2)is —OR^(GA), wherein R^(GA) is hydrogen or substituted or unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(5Y2) is —OH. In certainembodiments, R^(5Y2) is —NHR^(GA), wherein R^(GA) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.In certain embodiments, R^(5Y2) is —NH₂. In certain embodiments, R^(5Y2)is —N(R^(GA))₂, wherein R^(GA) is hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, or a nitrogen protecting group.

Various Combinations of Certain Embodiments

Various combinations of certain embodiments are further contemplatedherein.

For example, in certain embodiments, wherein R² is hydrogen or anon-hydrogen alpha substituent, provided is a compound of Formula(I-A1), (I-B1), or (I-C1):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R¹ is —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂OCH₃, or substituted orunsubstituted cyclopropyl. In certain embodiments, R² is —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, substituted orunsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments,R^(3a) and R^(3b) are both hydrogen. In certain embodiments, R^(3a) andR^(3b) are joined to form ═O (oxo). In certain embodiments, wherein RingB comprises a C₅-C₆ double bond, R^(4a) is hydrogen, fluoro, —CH₃, or—CF₃. In certain embodiments, wherein Ring B does not comprises a C₅-C₆double bond, both of R^(4a) and R^(4b) are hydrogen. In certainembodiments, wherein Ring B does not comprises a C₅-C₆ double bond, bothof R^(4a) and R^(4b) are —CH₃ or —CF₃. In certain embodiments, whereinRing B does not comprises a C₅-C₆ double bond, both of R^(4a) and R^(4b)are fluoro. In certain embodiments, wherein Ring B does not comprises aC₅-C₆ double bond, R^(4a) is a non-hydrogen substituent and R^(4b) ishydrogen.

In certain embodiments, wherein R² is hydrogen or a non-hydrogen betasubstituent, provided is a compound of Formula (I-A2), (I-B2), or(I-C2):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R¹ is —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂OCH₃, or substituted orunsubstituted cyclopropyl. In certain embodiments, R² is —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, substituted orunsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments,R^(3a) and R^(3b) are both hydrogen. In certain embodiments, R^(3a) andR^(3b) are joined to form ═O (oxo). In certain embodiments, wherein RingB comprises a C₅-C₆ double bond, R^(4a) is hydrogen, fluoro, —CH₃, or—CF₃. In certain embodiments, wherein Ring B does not comprises a C₅-C₆double bond, both of R^(4a) and R^(4b) are hydrogen. In certainembodiments, wherein Ring B does not comprises a C₅-C₆ double bond, bothof R^(4a) and R^(4b) are —CH₃ or —CF₃. In certain embodiments, whereinRing B does not comprises a C₅-C₆ double bond, both of R^(4a) and R^(4b)are fluoro. In certain embodiments, wherein Ring B does not comprises aC₅-C₆ double bond, R^(4a) is a non-hydrogen substituent and R^(4b) ishydrogen.

In certain embodiments, wherein R^(3a) is hydrogen or a non-hydrogenalpha substituent, and R^(3b) is hydrogen, provided is a compound ofFormula (I-A3), (I-B3), or (I-C3):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R¹ is —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂OCH₃, or substituted orunsubstituted cyclopropyl. In certain embodiments, R² is —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, substituted orunsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R²is a non-hydrogen substituent in the alpha configuration. In certainembodiments, R² is a non-hydrogen substituent in the beta configuration.In certain embodiments, wherein Ring B comprises a C₅-C₆ double bond,R^(4a) is hydrogen, fluoro, —CH₃, or —CF₃. In certain embodiments,wherein Ring B does not comprises a C₅-C₆ double bond, both of R^(4a)and R^(4b) are hydrogen. In certain embodiments, wherein Ring B does notcomprises a C₅-C₆ double bond, both of R^(4a) and R^(4b) are —CH₃ or—CF₃. In certain embodiments, wherein Ring B does not comprises a C₅-C₆double bond, both of R^(4a) and R^(4b) are fluoro. In certainembodiments, wherein Ring B does not comprises a C₅-C₆ double bond,R^(4a) is a non-hydrogen substituent and R^(4b) is hydrogen.

In certain embodiments, wherein R^(3a) is hydrogen or a non-hydrogenbeta substituent, and R^(3b) is hydrogen, provided is a compound ofFormula (I-A4), (I-B4), or (I-C4):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R¹ is —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂OCH₃, or substituted orunsubstituted cyclopropyl. In certain embodiments, R² is —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, substituted orunsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R²is a non-hydrogen substituent in the alpha configuration. In certainembodiments, R² is a non-hydrogen substituent in the beta configuration.In certain embodiments, wherein Ring B comprises a C₅-C₆ double bond,R^(4a) is hydrogen, fluoro, —CH₃, or —CF₃. In certain embodiments,wherein Ring B does not comprises a C₅-C₆ double bond, both of R^(4a)and R^(4b) are hydrogen. In certain embodiments, wherein Ring B does notcomprises a C₅-C₆ double bond, both of R^(4a) and R^(4b) are —CH₃ or—CF₃. In certain embodiments, wherein Ring B does not comprises a C₅-C₆double bond, both of R^(4a) and R^(4b) are fluoro. In certainembodiments, wherein Ring B does not comprises a C₅-C₆ double bond,R^(4a) is a non-hydrogen substituent and R^(4b) is hydrogen.

In certain embodiments, wherein R^(3a) and R^(3b) are joined to form anoxo group, provided is a compound of Formula (I-A5), (I-B5), or (I-C5):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R¹ is —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂OCH₃, or substituted orunsubstituted cyclopropyl. In certain embodiments, R² is —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, substituted orunsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R²is a non-hydrogen substituent in the alpha configuration. In certainembodiments, R² is a non-hydrogen substituent in the beta configuration.In certain embodiments, wherein Ring B comprises a C₅-C₆ double bond,R^(4a) is hydrogen, fluoro, —CH₃, or —CF₃. In certain embodiments,wherein Ring B does not comprises a C₅-C₆ double bond, both of R^(4a)and R^(4b) are hydrogen. In certain embodiments, wherein Ring B does notcomprises a C₅-C₆ double bond, both of R^(4a) and R^(4b) are —CH₃ or—CF₃. In certain embodiments, wherein Ring B does not comprises a C₅-C₆double bond, both of R^(4a) and R^(4b) are fluoro. In certainembodiments, wherein Ring B does not comprises a C₅-C₆ double bond,R^(4a) is a non-hydrogen substituent and R^(4b) is hydrogen.

In certain embodiments, wherein R^(4a) is a non-hydrogen substituent,provided is a compound of Formula (I-A6) or (I-B6):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R¹ is —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂OCH₃, or substituted orunsubstituted cyclopropyl. In certain embodiments, R² is —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, substituted orunsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R²is a non-hydrogen substituent in the alpha configuration. In certainembodiments, R² is a non-hydrogen substituent in the beta configuration.In certain embodiments, R^(3a) and R^(3b) are both hydrogen. In certainembodiments, R^(3a) and R^(3b) are joined to form ═O (oxo). In certainembodiments, R^(4a) is fluoro, —CH₃, or —CF₃ and R^(4b) is hydrogen. Incertain embodiments, R^(4b) is fluoro, —CH₃, or —CF₃ and R^(4a) ishydrogen. In certain embodiments, both of R^(4a) and R^(4b) are —CH₃ or—CF₃. In certain embodiments, both of R^(4a) and R^(4b) are fluoro.

In certain embodiments, a compound of Formula (I) is of one of thefollowing formulae:

In certain embodiments, a compound of Formula (I) is selected from thegroup consisting of:

or pharmaceutically acceptable salts thereof.

Pharmaceutical Compositions

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the present invention (also referred to as the“active ingredient”) and a pharmaceutically acceptable excipient. Incertain embodiments, the pharmaceutical composition comprises aneffective amount of the active ingredient. In certain embodiments, thepharmaceutical composition comprises a therapeutically effective amountof the active ingredient. In certain embodiments, the pharmaceuticalcomposition comprises a prophylactically effective amount of the activeingredient.

The pharmaceutical compositions provided herein can be administered by avariety of routes including, but not limited to, oral (enteral)administration, parenteral (by injection) administration, rectaladministration, transdermal administration, intradermal administration,intrathecal administration, subcutaneous (SC) administration,intravenous (IV) administration, intramuscular (IM) administration, andintranasal administration.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc, or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compostions of the present invention may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to raise the concentration of the compound in the bloodto an effective level. The placement of the bolus dose depends on thesystemic levels of the active ingredient desired throughout the body,e.g., an intramuscular or subcutaneous bolus dose allows a slow releaseof the active ingredient, while a bolus delivered directly to the veins(e.g., through an IV drip) allows a much faster delivery which quicklyraises the concentration of the active ingredient in the blood to aneffective level. In other embodiments, the pharmaceutical compositionmay be administered as a continuous infusion, e.g., by IV drip, toprovide maintenance of a steady-state concentration of the activeingredient in the subject's body. Furthermore, in still yet otherembodiments, the pharmaceutical composition may be administered as firstas a bolus dose, followed by continuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or excipients and processing aids helpful for forming thedesired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of thecompound provided herein, with preferred doses each providing from about0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, preferably fromabout 0.1 to about 20% by weight, preferably from about 0.1 to about 10%by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as aointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional ingredients to enhance thedermal penetration of stability of the active ingredients orFormulation. All such known transdermal formulations and ingredients areincluded within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of the present invention can also be administered insustained release forms or from sustained release drug delivery systems.A description of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableformulations of a compound of the present invention. In one embodiment,the formulation comprises water. In another embodiment, the formulationcomprises a cyclodextrin derivative. The most common cyclodextrins areα-, β- and γ-cyclodextrins consisting of 6, 7 and 8 a-1,4-linked glucoseunits, respectively, optionally comprising one or more substituents onthe linked sugar moieties, which include, but are not limited to,methylated, hydroxyalkylated, acylated, and sulfoalkylethersubstitution. In certain embodiments, the cyclodextrin is a sulfoalkylether β-cyclodextrin, e.g., for example, sulfobutyl etherβ-cyclodextrin, also known as Captisol□. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the formulation compriseshexapropyl-b-cyclodextrin (e.g., 10-50% in water).

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound of the present invention. The acidwhich may be used to prepare the pharmaceutically acceptable salt isthat which forms a non-toxic acid addition salt, i.e., a salt containingpharmacologically acceptable anions such as the hydrochloride,hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate,acetate, lactate, citrate, tartrate, succinate, maleate, fumarate,benzoate, para-toluenesulfonate, and the like.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisinvention. The present invention, however, is not limited to thefollowing pharmaceutical compositions.

Exemplary Formulation 1—Tablets:

A compound of the present invention may be admixed as a dry powder witha dry gelatin binder in an approximate 1:2 weight ratio. A minor amountof magnesium stearate is added as a lubricant. The mixture is formedinto 240-270 mg tablets (80-90 mg of active compound per tablet) in atablet press.

Exemplary Formulation 2—Capsules:

A compound of the present invention may be admixed as a dry powder witha starch diluent in an approximate 1:1 weight ratio. The mixture isfilled into 250 mg capsules (125 mg of active compound per capsule).

Exemplary Formulation 3—Liquid:

A compound of the present invention (125 mg) may be admixed with sucrose(1.75 g) and xanthan gum (4 mg) and the resultant mixture may beblended, passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of microcrystalline cellulose and sodiumcarboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10mg), flavor, and color are diluted with water and added with stirring.Sufficient water may then be added to produce a total volume of 5 mL.

Exemplary Formulation 4—Tablets:

A compound of the present invention may be admixed as a dry powder witha dry gelatin binder in an approximate 1:2 weight ratio. A minor amountof magnesium stearate is added as a lubricant. The mixture is formedinto 450-900 mg tablets (150-300 mg of active compound) in a tabletpress.

Exemplary Formulation 5—Injection:

A compound of the present invention may be dissolved or suspended in abuffered sterile saline injectable aqueous medium to a concentration ofapproximately 5 mg/mL.

Exemplary Formulation 6—Tablets:

A compound of the present invention may be admixed as a dry powder witha dry gelatin binder in an approximate 1:2 weight ratio. A minor amountof magnesium stearate is added as a lubricant. The mixture is formedinto 90-150 mg tablets (30-50 mg of active compound per tablet) in atablet press.

Exemplary Formulation 7—Tablets:

A compound of the present invention may be admixed as a dry powder witha dry gelatin binder in an approximate 1:2 weight ratio. A minor amountof magnesium stearate is added as a lubricant. The mixture is formedinto 30-90 mg tablets (10-30 mg of active compound per tablet) in atablet press.

Exemplary Formulation 8—Tablets:

A compound of the present invention may be admixed as a dry powder witha dry gelatin binder in an approximate 1:2 weight ratio. A minor amountof magnesium stearate is added as a lubricant. The mixture is formedinto 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in atablet press.

Exemplary Formulation 9—Tablets:

A compound of the present invention may be admixed as a dry powder witha dry gelatin binder in an approximate 1:2 weight ratio. A minor amountof magnesium stearate is added as a lubricant. The mixture is formedinto 150-240 mg tablets (50-80 mg of active compound per tablet) in atablet press.

Exemplary Formulation 10—Tablets:

A compound of the present invention may be admixed as a dry powder witha dry gelatin binder in an approximate 1:2 weight ratio. A minor amountof magnesium stearate is added as a lubricant. The mixture is formedinto 270-450 mg tablets (90-150 mg of active compound per tablet) in atablet press.

Methods of Use and Treatment

As generally described herein, the present invention is directed toC21-substituted neuroactive steroids designed, for example, to act asGABA modulators. In certain embodiments, such compounds are envisionedto be useful as therapeutic agents for the inducement of anesthesiaand/or sedation in a subject. In some embodiments, such compounds areenvisioned to be useful as therapeutic agents for treating a CNS-relateddisorder (e.g., sleep disorder, a mood disorder, a schizophreniaspectrum disorder, a convulsive disorder, a disorder of memory and/orcognition, a movement disorder, a personality disorder, autism spectrumdisorder, pain, traumatic brain injury, a vascular disease, a substanceabuse disorder and/or withdrawal syndrome, or tinnitus) in a subject inneed (e.g., a subject with Rett syndrome, Fragile X syndrome, orAngelman syndrome).

Thus, in one aspect, the present invention provides a method of inducingsedation and/or anesthesia in a subject, comprising administering to thesubject an effective amount of a compound of the present invention or acomposition thereof. In certain embodiments, the compound isadministered by intravenous administration.

Earlier studies (see, e.g., Gee et al., European Journal ofPharmacology, 136:419-423 (1987)) demonstrated that certain3α-hydroxylated steroids are orders of magnitude more potent asmodulators of the GABA receptor complex (GRC) than others had reported(see, e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison etal., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska et al. andHarrison et al. taught that 3α-hydroxylated-5-reduced steroids are onlycapable of much lower levels of effectiveness. In vitro and in vivoexperimental data have now demonstrated that the high potency of thesesteroids allows them to be therapeutically useful in the modulation ofbrain excitability via the GRC (see, e.g., Gee et al., European Journalof Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology118(1):65-71 (1995)).

Various synthetic steroids have also been prepared as neuroactivesteroids. See, for example, U.S. Pat. No. 5,232,917, which disclosesneuroactive steroid compounds useful in treating stress, anxiety,insomnia, seizure disorders, and mood disorders, that are amenable toGRC-active agents, such as depression, in a therapeutically beneficialmanner. Furthermore, it has been previously demonstrated that thesesteroids interact at a unique site on the GRC which is distinct fromother known sites of interaction (e.g., barbiturates, benzodiazepines,and GABA) where therapeutically beneficial effects on stress, anxiety,sleep, mood disorders and seizure disorders have been previouslyelicited (see, e.g., Gee, K. W. and Yamamura, H. I., “Benzodiazepinesand Barbiturates: Drugs for the Treatment of Anxiety, Insomnia andSeizure Disorders,” in Central Nervous System Disorders, Horvell, ed.,Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, K. G. and Morselli,P. L., “Psychopharmacology of GABAergic Drugs,” in Psychopharmacology:The Third Generation of Progress, H. Y. Meltzer, ed., Raven Press, N.Y.(1987), pp. 183-195; and Gee et al., European Journal of Pharmacology,136:419-423 (1987). These compounds are desirable for their duration,potency, and oral activity (along with other forms of administration).

Compounds of the present invention, as described herein, are generallydesigned to modulate GABA function, and therefore to act as neuroactivesteroids for the treatment and prevention of CNS-related conditions in asubject. Modulation, as used herein, refers to the inhibition orpotentiation of GABA receptor function. Accordingly, the compounds andpharmaceutical compositions provided herein find use as therapeutics forpreventing and/or treating CNS conditions in mammals including humansand non-human mammals. Thus, and as stated earlier, the presentinvention includes within its scope, and extends to, the recited methodsof treatment, as well as to the compounds for such methods, and to theuse of such compounds for the preparation of medicaments useful for suchmethods.

Exemplary CNS conditions related to GABA-modulation include, but are notlimited to, sleep disorders [e.g., insomnia], mood disorders [e.g.,depression, dysthymic disorder (e.g., mild depression), bipolar disorder(e.g., I and/or II), anxiety disorders (e.g., generalized anxietydisorder (GAD), social anxiety disorder), stress, post-traumatic stressdisorder (PTSD), compulsive disorders (e.g., obsessive compulsivedisorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia,schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g.,status epilepticus (SE)), seizures], disorders of memory and/orcognition [e.g., attention disorders (e.g., attention deficithyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's typedementia, Lewis body type dementia, vascular type dementia], movementdisorders [e.g., Huntington's disease, Parkinson's disease], personalitydisorders [e.g., anti-social personality disorder, obsessive compulsivepersonality disorder], autism spectrum disorders (ASD) [e.g., autism,monogenetic causes of autism such as synaptophathy's, e.g., Rettsyndrome, Fragile X syndrome, Angelman syndrome], pain [e.g.,neuropathic pain, injury related pain syndromes, acute pain, chronicpain], traumatic brain injury (TBI), vascular diseases [e.g., stroke,ischemia, vascular malformations], substance abuse disorders and/orwithdrawal syndromes [e.g., addition to opiates, cocaine, and/oralcohol], and tinnitus.

In yet another aspect, provided is a combination of a compound of thepresent invention and another pharmacologically active agent. Thecompounds provided herein can be administered as the sole active agentor they can be administered in combination with other agents.Administration in combination can proceed by any technique apparent tothose of skill in the art including, for example, separate, sequential,concurrent and alternating administration.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of the present invention tothe subject.

In yet another aspect, provided is a method of treating or preventingstress or anxiety in a subject, comprising administering to the subjectin need of such treatment an effective amount of a compound of thepresent invention, or a composition thereof.

In yet another aspect, provided is a method of alleviating or preventingseizure activity in a subject, comprising administering to the subjectin need of such treatment an effective amount of a compound of thepresent invention.

In yet another aspect, provided is a method of alleviating or preventinginsomnia in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention, or a composition thereof.

In yet another aspect, provided is a method of inducing sleep andmaintaining substantially the level of REM sleep that is found in normalsleep, wherein substantial rebound insomnia is not induced, comprisingadministering an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of alleviating or preventingPMS or PND in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of treating or preventingmood disorders in a subject, comprising administering to the subject inneed of such treatment an effective amount of a compound of the presentinvention. In certain embodiments the mood disorder is depression.

In yet another aspect, provided is a method of inducing anesthesia in asubject, comprising administering to the subject an effective amount ofa compound of the present invention.

In yet another aspect, provided is a method of cognition enhancement ortreating memory disorder by administering to the subject atherapeutically effective amount of a compound of the present invention.In certain embodiments, the disorder is Alzheimer's disease. In certainembodiments, the disorder is Rett syndrome.

In yet another aspect, provided is a method of treating attentiondisorders by administering to the subject a therapeutically effectiveamount of a compound of the present invention. In certain embodiments,the attention disorder is ADHD.

In certain embodiments, the compound is administered to the subjectchronically. In certain embodiments, the compound is administered to thesubject orally, subcutaneously, intramuscularly, or intravenously.

Anesthesia/Sedation

Anesthesia is a pharmacologically induced and reversible state ofamnesia, analgesia, loss of responsiveness, loss of skeletal musclereflexes, decreased stress response, or all of these simultaneously.These effects can be obtained from a single drug which alone providesthe correct combination of effects, or occasionally with a combinationof drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achievevery specific combinations of results. Anesthesia allows patients toundergo surgery and other procedures without the distress and pain theywould otherwise experience.

Sedation is the reduction of irritability or agitation by administrationof a pharmacological agent, generally to facilitate a medical procedureor diagnostic procedure.

Sedation and analgesia include a continuum of states of consciousnessranging from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is adrug-induced state during which the patient responds normally to verbalcommands. Cognitive function and coordination may be impaired.Ventilatory and cardiovascular functions are typically unaffected.

Moderate sedation/analgesia (conscious sedation) is a drug-induceddepression of consciousness during which the patient respondspurposefully to verbal command, either alone or accompanied by lighttactile stimulation. No interventions are usually necessary to maintaina patent airway. Spontaneous ventilation is typically adequate.Cardiovascular function is usually maintained.

Deep sedation/analgesia is a drug-induced depression of consciousnessduring which the patient cannot be easily aroused, but respondspurposefully (not a reflex withdrawal from a painful stimulus) followingrepeated or painful stimulation. Independent ventilatory function may beimpaired and the patient may require assistance to maintain a patentairway. Spontaneous ventilation may be inadequate. Cardiovascularfunction is usually maintained.

General anesthesia is a drug-induced loss of consciousness during whichthe patient is not arousable, even to painful stimuli. The ability tomaintain independent ventilatory function is often impaired andassistance is often required to maintain a patent airway. Positivepressure ventilation may be required due to depressed spontaneousventilation or drug-induced depression of neuromuscular function.Cardiovascular function may be impaired.

Sedation in the intensive care unit (ICU) allows the depression ofpatients' awareness of the environment and reduction of their responseto external stimulation. It can play a role in the care of thecritically ill patient, and encompasses a wide spectrum of symptomcontrol that will vary between patients, and among individualsthroughout the course of their illnesses. Heavy sedation in criticalcare has been used to facilitate endotracheal tube tolerance andventilator synchronization, often with neuromuscular blocking agents.

In some embodiments, sedation (e.g., long-term sedation, continuoussedation) is induced and maintained in the ICU for a prolonged period oftime (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1month, 2 months). Long-term sedation agents may have long duration ofaction. Sedation agents in the ICU may have short elimination half-life.

Procedural sedation and analgesia, also referred to as conscioussedation, is a technique of administering sedatives or dissociativeagents with or without analgesics to induce a state that allows asubject to tolerate unpleasant procedures while maintainingcardiorespiratory function.

Anxiety Disorders

Anxiety disorder is a blanket term covering several different forms ofabnormal and pathological fear and anxiety. Current psychiatricdiagnostic criteria recognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes. Often,normal changes in heartbeat are noticed by a panic sufferer, leadingthem to think something is wrong with their heart or they are about tohave another panic attack. In some cases, a heightened awareness(hypervigilance) of body functioning occurs during panic attacks,wherein any perceived physiological change is interpreted as a possiblelife threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of Phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

Neurodegenerative Diseases and Disorders

The term “neurodegenerative disease” includes diseases and disordersthat are associated with the progressive loss of structure or functionof neurons, or death of neurons. Neurodegenerative diseases anddisorders include, but are not limited to, Alzheimer's disease(including the associated symptoms of mild, moderate, or severecognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic andischemic injuries; ataxia and convulsion (including for the treatmentand prevention and prevention of seizures that are caused byschizoaffective disorder or by drugs used to treat schizophrenia);benign forgetfulness; brain edema; cerebellar ataxia including McLeodneuroacanthocytosis syndrome (MLS); closed head injury; coma; contusiveinjuries (e.g., spinal cord injury and head injury); dementias includingmulti-infarct dementia and senile dementia; disturbances ofconsciousness; Down syndrome; drug-induced or medication-inducedParkinsonism (such as neuroleptic-induced acute akathisia, acutedystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignantsyndrome, or medication-induced postural tremor); epilepsy; fragile Xsyndrome; Gilles de la Tourette's syndrome; head trauma; hearingimpairment and loss; Huntington's disease; Lennox syndrome;levodopa-induced dyskinesia; mental retardation; movement disordersincluding akinesias and akinetic (rigid) syndromes (including basalganglia calcification, corticobasal degeneration, multiple systematrophy, Parkinsonism-ALS dementia complex, Parkinson's disease,postencephalitic parkinsonism, and progressively supranuclear palsy);muscular spasms and disorders associated with muscular spasticity orweakness including chorea (such as benign hereditary chorea,drug-induced chorea, hemiballism, Huntington's disease,neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea),dyskinesia (including tics such as complex tics, simple tics, andsymptomatic tics), myoclonus (including generalized myoclonus and focalcyloclonus), tremor (such as rest tremor, postural tremor, and intentiontremor) and dystonia (including axial dystonia, dystonic writer's cramp,hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such asblepharospasm, oromandibular dystonia, and spasmodic dysphonia andtorticollis); neuronal damage including ocular damage, retinopathy ormacular degeneration of the eye; neurotoxic injury which followscerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebralischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia,perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure;status epilecticus; stroke; tinnitus; tubular sclerosis, and viralinfection induced neurodegeneration (e.g., caused by acquiredimmunodeficiency syndrome (AIDS) and encephalopathies).Neurodegenerative diseases also include, but are not limited to,neurotoxic injury which follows cerebral stroke, thromboembolic stroke,hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia,amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methodsof treating or preventing a neurodegenerative disease also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

Epilepsy

Epilepsy is a brain disorder characterized by repeated seizures overtime. Types of epilepsy can include, but are not limited to generalizedepilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy,epilepsy with grand-mal seizures on awakening, West syndrome,Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy,frontal lobe epilepsy, benign focal epilepsy of childhood.

Status Epilepticus (SE)

Status epilepticus (SE) can include, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges. Convulsive status epilepticus is characterized by thepresence of convulsive status epileptic seizures, and can include earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus. Early statusepilepticus is treated with a first line therapy. Established statusepilepticus is characterized by status epileptic seizures which persistdespite treatment with a first line therapy, and a second line therapyis administered. Refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline and a second line therapy, and a general anesthetic is generallyadministered. Super refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline therapy, a second line therapy, and a general anesthetic for 24hours or more.

Non-convulsive status epilepticus can include, e.g., focalnon-convulsive status epilepticus, e.g., complex partial non-convulsivestatus epilepticus, simple partial non-convulsive status epilepticus,subtle non-convulsive status epilepticus; generalized non-convulsivestatus epilepticus, e.g., late onset absence non-convulsive statusepilepticus, atypical absence non-convulsive status epilepticus, ortypical absence non-convulsive status epilepticus.

Compositions described herein can also be administered as a prophylacticto a subject having a CNS disorder e.g., a traumatic brain injury,status epilepticus, e.g., convulsive status epilepticus, e.g., earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus; non-convulsive statusepilepticus, e.g., generalized status epilepticus, complex partialstatus epilepticus; generalized periodic epileptiform discharges; andperiodic lateralized epileptiform discharges; prior to the onset of aseizure.

Seizure

A seizure is the physical findings or changes in behavior that occurafter an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with “convulsion.” Convulsionsare when a person's body shakes rapidly and uncontrollably. Duringconvulsions, the person's muscles contract and relax repeatedly.

Based on the type of behavior and brain activity, seizures are dividedinto two broad categories: generalized and partial (also called local orfocal). Classifying the type of seizure helps doctors diagnose whetheror not a patient has epilepsy.

Generalized seizures are produced by electrical impulses from throughoutthe entire brain, whereas partial seizures are produced (at leastinitially) by electrical impulses in a relatively small part of thebrain. The part of the brain generating the seizures is sometimes calledthe focus.

There are six types of generalized seizures. The most common anddramatic, and therefore the most well known, is the generalizedconvulsion, also called the grand-mal seizure. In this type of seizure,the patient loses consciousness and usually collapses. The loss ofconsciousness is followed by generalized body stiffening (called the“tonic” phase of the seizure) for 30 to 60 seconds, then by violentjerking (the “clonic” phase) for 30 to 60 seconds, after which thepatient goes into a deep sleep (the “postictal” or after-seizure phase).During grand-mal seizures, injuries and accidents may occur, such astongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a fewseconds) with few or no symptoms. The patient, most often a child,typically interrupts an activity and stares blankly. These seizuresbegin and end abruptly and may occur several times a day. Patients areusually not aware that they are having a seizure, except that they maybe aware of “losing time.”

Myoclonic seizures consist of sporadic jerks, usually on both sides ofthe body. Patients sometimes describe the jerks as brief electricalshocks. When violent, these seizures may result in dropping orinvoluntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sidesof the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone,particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acuterepetitive seizures; cluster seizures; continuous seizures; unremittingseizures; prolonged seizures; recurrent seizures; status epilepticusseizures, e.g., refractory convulsive status epilepticus, non-convulsivestatus epilepticus seizures; refractory seizures; myoclonic seizures;tonic seizures; tonic-clonic seizures; simple partial seizures; complexpartial seizures; secondarily generalized seizures; atypical absenceseizures; absence seizures; atonic seizures; benign Rolandic seizures;febrile seizures; emotional seizures; focal seizures; gelastic seizures;generalized onset seizures; infantile spasms; Jacksonian seizures;massive bilateral myoclonus seizures; multifocal seizures; neonatalonset seizures; nocturnal seizures; occipital lobe seizures; posttraumatic seizures; subtle seizures; Sylvan seizures; visual reflexseizures; or withdrawal seizures.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Materials and Methods

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)recrystallization, column chromatography, HPLC, or supercritical fluidchromatography (SFC). The following schemes are presented with detailsas to the preparation of representative substituted biarylamides thathave been listed herein. The compounds provided herein may be preparedfrom known or commercially available starting materials and reagents byone skilled in the art of organic synthesis. Exemplary chiral columnsavailable for use in the separation/purification of theenantiomers/diastereomers provided herein include, but are not limitedto, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD,CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ andCHIRALCEL® OK.

¹H-NMR reported herein may be a partial representation of the full NMRspectrum of a compound, e.g., a compound described herein. For example,the reported ¹H NMR may exclude the region between δ (ppm) of about 1 toabout 2.5 ppm. Copies of full ¹H-NMR spectrum for representativeexamples are provided in the Figures.

General method for supercritical fluid chromatography (SFC): SFCpurification was carried out using a Thar 200 preparative SFC instrumentequipped with a ChiralPak AD-10 μM, 200×50 mm ID. The compounds wereseparated eluting with mixtures of carbon dioxide and methanol orethanol (e.g., 20-35% methanol or ethanol and 0.1% ammonium hydroxide)at a flow rate of 55-200 mL/min and monitored at 220 nm wavelength.

Exemplary general method for preparative HPLC: Column: Waters RBridgeprep 10 μm C18, 19*250 mm. Mobile phase: acetonitrile, water (NH₄HCO₃)(30 L water, 24 g NH4HCO3, 30 mL NH₃.H₂O). Flow rate: 25 mL/min

Exemplary general method for analytical HPLC: Mobile phase: A: water (10mM NH₄HCO₃), B: acetonitrileGradient: 5%-95% B in 1.6 or 2 min Flowrate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 μm at 45 C.

Synthetic Procedures

The compounds of the invention can be prepared in accordance withmethods described in the art (Upasani et al., J. Med. Chem. 1997,40:73-84; and Hogenkamp et al., J. Med. Chem. 1997, 40:61-72) and usingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art. In some embodiments, compoundsdescribed herein can be prepared using methods shown in general Schemes1-3, comprising a nucleophilic substitution of 19-nor pregnane bromidewith a nucleophile. In certain embodiments, the nucleophile reacts withthe 19-nor pregnane bromide in the presence of K₂CO₃ in THF.

Example 1. Synthesis of SA and SA Intermediates

Synthesis of compound SA-B.

Compound SA (50 g, 184 mmol) and palladium black (2.5 g) intetrahydrofuran (300 mL) and concentrated hydrobromic acid (1.0 mL) washydrogenated with 10 atm hydrogen. After stirring at room temperaturefor 24 h, the mixture was filtered through a pad of celite and thefiltrate was concentrated in vacuo to afford the crude compound.Recrystallization from acetone gave compound SA-B (42.0 g, yield: 83.4%)as white powder.

¹H NMR: (400 MHz, CDCl3) δ 2.45-2.41 (m, 1H), 2.11-3.44 (m, 2H), 3.24(s, 3H), 2.18-2.15 (m, 1H), 2.01-1.95 (m, 1H), 1.81-1.57 (m, 7H),1.53-1.37 (m, 7H), 1.29-1.13 (m, 3H), 1.13-0.90 (m, 2H), 0.89 (s, 3H).

Synthesis of Compound SA-C.

A solution of SA-B (42.0 g, 153.06 mmol) in 600 mL anhydrous toluene wasadded dropwise to the methyl aluminumbis(2,6-di-tert-butyl-4-methylphenoxide (MAD) (459.19 mmol, 3.0 eq,freshly prepared) solution under N₂ at −78° C. After the addition wascompleted, the reaction mixture was stirred for 1 hr at −78° C. Then 3.0M MeMgBr (153.06 mL, 459.19 mmol) was slowly added dropwise to the abovemixture under N₂ at −78° C. Then the reaction mixture was stirred for 3hr at this temperature. TLC (petroleum ether/ethyl acetatePetroleumether/ethyl acetate=3:1) showed the reaction was completed. Thensaturated aqueous NH₄Cl was slowly added dropwise to the above mixtureat −78° C. After the addition was completed, the mixture was filtered,the filter cake was washed with EtOAc, the organic layer was washed withwater and brine, dried over anhydrous Na₂SO₄, filtered and concentrated,purified by flash Chromatography on silica gel (Petroleum ether/ethylacetate20:1 to 3:1) to afford compound SA-C (40.2 g, yield: 90.4%) aswhite powder. ¹H NMR: (400 MHz, CDCl3) δ 2.47-2.41 (m, 1H), 2.13-2.03(m, 1H), 1.96-1.74 (m, 6H), 1.70-1.62 (m, 1H), 1.54-1.47 (m, 3H),1.45-1.37 (m, 4H), 1.35-1.23 (m, 8H), 1.22-1.10 (m, 2H), 1.10-1.01 (m,1H), 0.87 (s, 3H).

Synthesis of Compound SA-D.

To a solution of PPh₃EtBr (204.52 g, 550.89 mmol) in THF (500 mL) wasadded a solution of t-BuOK (61.82 g, 550.89 mmol) in THF (300 mL) at 0°C. After the addition was completed, the reaction mixture was stirredfor 1 h 60° C., then SA-C (40.0 g, 137.72 mmol) dissolved in THF (300mL) was added dropwise at 60° C. The reaction mixture was heated to 60°C. for 18 h. The reaction mixture was cooled to room temperature andquenched with Sat. NH₄Cl, extracted with EtOAc (3*500 mL). The combinedorganic layers were washed with brine, dried and concentrated to givethe crude product, which was purified by a flash column chromatography(Petroleum ether/ethyl acetate50:1 to 10:1) to afford compound SA-D(38.4 g, yield: 92%) as a white powder. ¹H NMR: (400 MHz, CDCl3) δ5.17-5.06 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.13 (m, 2H), 1.89-1.80 (m,3H), 1.76-1.61 (m, 6H), 1.55-1.43 (m, 4H), 1.42-1.34 (m, 3H), 1.33-1.26(m, 6H), 1.22-1.05 (m, 5H), 0.87 (s, 3H).

Synthesis of Compound SA-E.

To a solution of SA-D (38.0 g, 125.62 mmol) in dry THF (800 mL) wasadded dropwise a solution of BH₃.Me₂S (126 mL, 1.26 mol) under ice-bath.After the addition was completed, the reaction mixture was stirred for 3h at room temperature (14-20° C.). TLC (petroleum ether/ethyl acetate3:1) showed the reaction was completed. The mixture was cooled to 0° C.and 3.0 M aqueous NaOH solution (400 mL) followed by 30% aqueous H₂O₂(30%, 300 mL) was added. The mixture was stirred for 2 h at roomtemperature (14-20° C.), and then filtered, extracted with EtOAc (3*500mL). The combined organic layers were washed with saturated aqueousNa₂S₂O₃, brine, dried over Na₂SO₄ and concentrated in vacuum to give thecrude product (43 g, crude) as colorless oil. The crude product was usedin the next step without further purification.

Synthesis of Compound SA-F.

To a solution of SA-E (43.0 g, 134.16 mmol) in dichloromethane (800 mL)at 0° C. and PCC (53.8 g, 268.32 mmol) was added portion wise. Then thereaction mixture was stirred at room temperature (16-22° C.) for 3 h.TLC (Petroleum ether/ethyl acetate3:1) showed the reaction wascompleted, then the reaction mixture was filtered, washed with DCM. Theorganic phase was washed with saturated aqueous Na₂S₂O₃, brine, driedover Na₂SO₄ and concentrated in vacuum to give the crude product. Thecrude product was purified by a flash column chromatography (Petroleumether/ethyl acetate50:1 to 8:1) to afford compound SA-F (25.0 g, yield:62.5%, over two steps) as a white powder. ¹H NMR (SA-F): (400 MHz,CDCl3) δ 2.57-2.50 (m, 1H), 2.19-2.11 (m, 4H), 2.03-1.97 (m, 1H),1.89-1.80 (m, 3H), 1.76-1.58 (m, 5H), 1.47-1.42 (m, 3H), 1.35-1.19 (m,10H), 1.13-1.04 (m, 3H), 0.88-0.84 (m, 1H), 0.61 (s, 3H).

Synthesis of Compound SA.

To a solution of SA-F (10 g, 31.4 mmol) and aq. HBr (5 drops, 48% inwater) in 200 mL of MeOH was added dropwise bromine (5.52 g, 34.54mmol). The reaction mixture was stirred at 17° C. for 1.5 h. Theresulting solution was quenched with saturated aqueous NaHCO₃ at 0° C.and extracted with EtOAc (150 mL×2). The combined organic layers weredried and concentrated. The residue was purified by columnchromatography on silica gel eluted with (PE:EA=15:1 to 6:1) to affordcompound SA (9.5 g, yield: 76.14%) as a white solid. LC/MS: rt 5.4 min;m/z 379.0, 381.1, 396.1.

Example 2. Synthesis of SB and SB-J Intermediates

Synthesis of Compounds SB-B and SB-C.

Small pieces of lithium (7.63 g, 1.1 mol) were added to 2.7 L ofcondensed ammonia in a three neck flask at −70° C. As soon as alllithium was dissolved, the blue solution was warmed to −50° C. Asolution of 19-norandrost-4-ene-3,17-dione SB-A (1, 30 g, 110 mmol) andtert-BuOH (8.14 g, 110 mmol) in 800 ml of anhydrous tetrahydrofuran wasadded dropwise and stirred for 90 min until the reaction mixture turnedlight yellow. Ammonium chloride (70 g) was added and excess ammonia wasleft to evaporate. The residue was extracted with 0.5N HCl (500 mL) anddichloromethane (500 mL×2). The combined organic layers were washed withsaturated NaHCO₃ solution, dried over Na₂SO₄, filtered and concentratedto give a mixture of SB-B and SB-C (21 g, 70%) which was directly usedin the next step without further purification. A solution of SB-B andSB-C (21 g, 76 mmol) in 50 mL of anhydrous dichloromethane was added toa suspension of pyridinium chlorochromate (PCC) (32.8 g, 152 mmol) in450 mL of dichloromethane. After stirring at room temperature for 2 h,2N NaOH solution (500 mL) was added to the dark brown reaction mixtureand stirred for another 10 min. The resulting solution was extractedwith dichloromethane, the combined organic layers were washed with 2NHCl, brine, dried over Na₂SO₄, filtered and concentrated. The residuewas purified by chromatography on silica gel (petroleum ether/ethylacetate=20:1 to 10:1) to afford title compound SB-C (16.8 g, 80%) as awhite solid.

Synthesis of Compound SB-D.

To a solution of compound SB-C (16.8 g. 61.3 mmol) in methanol (250 mL)was added iodine (1.54 g, 6.1 mmol). After stirring at 60° C. for 12 h,the solvent was removed in vacuo. The crude product was dissolved indichloromethane (200 mL) and washed with saturated NaHCO₃ (150 mL),brine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by chromatography on basic alumina (petroleum ether/ethylacetate=100:1) to give compound SB-D (14 g, 43.8 mmol, 71%).

Synthesis of Compound SB-E.

To a suspension of t-BuOK (7.36 g, 65.7 mmol) in THF (100 mL) at 0° C.was added ethyltriphenylphosphonium bromide (26 g, 70 mmol) slowly.After stirring at 60° C. for 3 h, compound SB-D (7 g, 21.9 mmol) wasadded and the mixture was stirred at 60° C. for another 2 h. Aftercooling to room temperature, the reaction mixture was poured intosaturated ammonium chloride and extracted with EtOAc (2×500 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrate to afford the crude compound SB-E(7.36 g, 100%). The crude product was used in the next step withoutfurther purification.

Synthesis of Compound SB-F.

A solution of crude compound SB-E (7.36 g, 21.9 mmol) in THF (50 mL) wasacidified to pH=3 by 1N aqueous HCl. After stirring at room temperaturefor 12 h, the reaction mixture was extracted with ethyl acetate (250mL×3). The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated. The residue was purified bycolumn chromatography (petroleum ether/ethyl acetate=30:1 to 20:1) toafford compound SB-F (4.8 g, 16.7 mmol, 76% for two steps).

Synthesis of Compound SB-G.

To a solution of MeMgBr (28 mmol, 1M in THF) in THF (50 mL) at 0° C. wasadded a solution of compound SB-F (4.8 g, 16.8 mmol) in dry THF (10 mL)via syringe pump over 30 min. After stirring at 0° C. for 5 h, thereaction mixture was allowed to warm up and stirred at room temperatureovernight. The reaction mixture was quenched with iced-cold water andextracted with ethyl acetate (150 mL×3). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated. The white residue was purified by flash columnchromatography (petroleum ether/ethyl acetate=20:1 to 10:1) to givecompound SB-G (2.5 g, 8.28 mmol, 49%; Rf=0.35, PE:EtOAc=10:1).

Synthesis of Compound SB-H.

To a solution of compound SB-G (2 g, 6.62 mmol) in dry THF (50 mL) wasadded borane-tetrahydrofuran complex (20 mL; 1.0 M solution in THF).After stirring at room temperature for 1 hour, the reaction mixture wascooled in an ice bath then quenched slowly with 10% aqueous NaOH (10 mL)followed by 30% aqueous solution of H₂O₂ (12 mL). After stirring at roomtemperature for one hour, the mixture was extracted with EtOAc (3×100mL). The combined organic layers were washed with 10% aqueous Na₂S₂O₃(100 mL), brine (100 mL), dried over MgSO₄, filtered and concentrated toafford crude compound SB-H (2 g, 100%). The crude product was used inthe next step without further purification.

Synthesis of Compound SB-I.

To a solution of crude compound SB-H (2 g, 6.62 mmol) in 60 mL of wetdichloromethane (dichloromethane had been shaken with severalmilliliters of H₂O then separated from the water layer) was addedDess-Martin periodinate (5.5 g, 13 mmol). After stirring at roomtemperature for 24 h, the reaction mixture was extracted withdichloromethane (3×100 mL). The combined organic layers were washed with10% aqueous Na₂S₂O₃ (100 mL), brine (100 mL), dried over MgSO₄, filteredand concentrated. The residue was purified by chromatography on silicagel (petroleum ether/ethyl acetate=10:1 to 5:1) to afford compound SB-I(1 g, 3.14 mmol, 47% for two steps) as a white solid. ¹H NMR (400 MHz,CDCl₃), δ (ppm), 2.56 (t, 1H), 2.11 (s and m, 4H), 2.0 (dt, 1H), 1.8(dm, 2H), 1.54 (m, 6H) 1.43 (m, 1H), 1.34 (m, 2H), 1.20 (m, 12H), 0.7(m, 2H), 0.62 (s, 3H).

Synthesis of Intermediate SB.

To a solution of compound SB-I (600 mg, 1.89 mmol) in MeOH (20 mL) wasadded 5 drops of HBr (48%) followed by bromine (302 mg, 1.89 mmol).After stirring at room temperature for 1 h, the reaction mixture waspoured into ice-water then extracted with ethyl acetate (100 mL×3). Thecombined organic layers were washed with brine (200 mL), dried overMgSO₄, filtered and concentrated to give crude compound SB (600 mg).

Synthesis of Compound SB-J.

A solution of compound SB (600 mg, 1.5 mmol) in acetone 10 mL wastreated with CF₃COOH (6.8 mL) and Et₃N (9.5 mL). After refluxed for 30min, CF₃COONa salt (4.49 g, 33 mmol) was added in parts over a period of10 hr. The reaction mixture was allowed to cool to room temperature andthe solvent was removed in vaccuo. The residue was extracted with ethylacetate, dried over MgSO₄, filtered and concentrated. The mixture waspurified by chromatography on silica gel (petroleum ether/ethylacetate=10:1 to 3:1) to afford SB-J (300 mg, yield: 50% for two steps).

Example 3. Synthesis of Compound SA-1

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added1-methylpiperazine (25 mg, 0.227 mmol) and SA (36 mg, 0.09 mmol). Themixture was stirred at rt for 15 h. The reaction mixture was poured into 5 mL H₂O and extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified with by reverse-phase prep-HPLCto afford the title compound SA-1 as a white solid (12 mg, 37.8%).

Example 4. Synthesis of Compound SA-2

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was addedpiperidin-4-ol (30 mg, 0.29 mmol) and SA (36 mg, 0.09 mmol). The mixturewas stirred at rt for 15 h. The reaction mixture was poured in to 5 mLH₂O and extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue was purified with by reverse-phase prep-HPLC to afford thetitle compound SA-2 as a white solid (15 mg, 39.4%).

Example 5. Synthesis of Compound SA-3

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was addedpyrrolidin-3-ol (35 mg, 0.40 mmol) and SA (36 mg, 0.09 mmol). Themixture was stirred at rt for 15 h. The reaction mixture was poured into 5 mL H₂O and extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified with by reverse-phase prep-HPLCto afford the title compound SA-3 as a white solid (12 mg, 30%).

Example 6. Synthesis of Compound SA-4

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was addedazetidin-3-ol (35 mg, 0.48 mmol) and SA (36 mg, 0.09 mmol). The mixturewas stirred at rt for 15 h. The reaction mixture was poured in to 5 mLH₂O and extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue was purified with by reverse-phase prep-HPLC to afford thetitle compound SA-4 as a white solid (8 mg, 23.5%).

Example 7. Synthesis of Compound SA-5

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was addedpiperidin-3-ol (35 mg, 0.35 mmol) and SA (36 mg, 0.09 mmol). The mixturewas stirred at rt for 15 h. The reaction mixture was poured in to 5 mLH₂O and extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue was purified with by reverse-phase prep-HPLC to afford thetitle compound SA-5 as a white solid (10 mg, 26.3%).

Example 8. Synthesis of Compound SA-6

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added(R)-2-methylmorpholine (20 mg, 0.20 mmol) and SA (36 mg, 0.09 mmol). Themixture was stirred at rt for 15 h. The reaction mixture was poured into 5 mL H₂O and extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue mixture was purified with by reverse-phaseprep-HPLC to afford the title compound SA-6 as a white solid (11 mg,27.9%).

Example 9. Synthesis of Compound SA-7

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added(R)-2-methylmorpholine (20 mg, 0.20 mmol) and SA (36 mg, 0.09 mmol). Themixture was stirred at rt for 15 h. The reaction mixture was poured into 5 mL H₂O and extracted with sodium sulfate, filtered andconcentrated. The residue mixture was purified with by reverse-phaseprep-HPLC to afford the title compound SA-7 as a white solid (7 mg,17.7%).

Example 10. Synthesis of Compound SA-8

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added1-(methylsulfonyl)piperazine (38 mg, 0.23 mmol) and SA (36 mg, 0.09mmol). The mixture was stirred at RT for 15 h. The residue mixture waspoured in to 5 mL H₂O and extracted with EtOAc (2×10 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated. The residue mixture was purified with byreverse-phase prep-HPLC to afford the title compound SA-8 as a whitesolid (13 mg, 30%).

Example 11. Synthesis of Compound SA-9

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was addedN-methylpiperazine-1-carboxamide (33 mg, 0.23 mmol) and SA (36 mg, 0.09mmol). The mixture was stirred at RT for 15 h. The residue mixture waspoured in to 5 mL H₂O and extracted with EtOAc (2×10 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated. The residue mixture was purified with byreverse-phase prep-HPLC to afford the title compound SA-9 as a whitesolid (8 mg, 19%).

Example 12. Synthesis of Compound SA-10

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added1-propylpiperazine (29 mg, 0.23 mmol) and SA (36 mg, 0.09 mmol). Themixture was stirred at RT for 15 h. The residue mixture was poured in to5 mL H₂O and extracted with EtOAc (2×10 mL). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue mixture was purified with by reverse-phaseprep-HPLC to afford the title compound as a white solid (12 mg, 34%).

Example 13. Synthesis of Compound SA-11

To a suspension of K₂CO₃ (55 mg, 0.4 mmol) in THF (5 mL) was added1,4-oxazepane (41 mg, 0.4 mmol) and Compound SA (85 mg, 0.2 mmol). Themixture was stirred at RT for 15 h then the residue mixture was pouredinto 5 mL H₂O and extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue mixture was purified by reverse-phaseprep-HPLC to afford SA-11 as a white solid (7 mg, 8%). LC-MS: rt=2.32min, m/z=418.4 [M+H]⁺

Example 14. Synthesis of Compound SA-12

To a suspension of K₂CO₃ (55 mg, 0.4 mmol) in THF (5 mL) was added(R)-2-methylpiperidine (40 mg, 0.4 mmol) and Compound SA (85 mg, 0.2mmol). The mixture was stirred at RT for 15 h then the residue mixturewas poured into 5 mL H₂O and extracted with EtOAc (2×10 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue mixture was purified byreverse-phase prep-HPLC to afford SA-12 as a white solid (7 mg, 8%).LC-MS: rt=2.72 min, m/z=416.5 [M+H]⁺

Example 15. Synthesis of Compound SA-13

To a suspension of K₂CO₃ (55 mg, 0.4 mmol) in THF (5 mL) was added(R)-3-methylpyrrolidine (34 mg, 0.4 mmol) and Compound SA (85 mg, 0.2mmol). The mixture was stirred at RT for 15 h then the residue mixturewas poured into 5 mL H₂O and extracted with EtOAc (2×10 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue mixture was purified byreverse-phase prep-HPLC to afford SA-13 as a white solid (4 mg, 5%).LC-MS: rt=2.56 min, m/z=402.4 [M+H]⁺

Example 16. Synthesis of Compound SA-14

To a suspension of K₂CO₃ (50 mg, 0.36 mmol) in THF (5 mL) was added(2S,6S)-2,6-dimethylmorpholine (41 mg, 0.27 mmol) and SA (100 mg, 0.09mmol). The mixture was stirred at rt for 15 h. Then the reaction mixturewas poured into 5 mL H₂O and extracted with EtOAc (2×10 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue was purified with byreverse-phase prep-HPLC to afford the title compound as a white solid,SA-14 (12 mg, 11.2%), LC-MS: rt=2.49 min, m/z=432.4 (M⁺+1)

Example 18. Synthesis of Compound SA-16

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added1-(piperazin-1-yl)ethanone (20 mg, 0.156 mmol) and SA (36 mg, 0.09mmol). The mixture was stirred at rt for 15 h. The reaction mixture waspoured in to 5 mL H₂O and extracted with EtOAc (2×10 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated. The residue was purified with byreverse-phase prep-HPLC to afford the title compound SA-16 as a whitesolid (9 mg, 22.5%). LC/MS: rt=2.22 min; m/z=445.3 [M+H].

Example 19. Synthesis of Compound SA-17

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was addedpiperazine (25 mg, 0.29 mmol) and SA (36 mg, 0.09 mmol). The mixture wasstirred at rt for 15 h. The reaction mixture was poured in to 5 mL H₂Oand extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue was purified with by reverse-phase prep-HPLC to afford thetitle compound SA-17 as a white solid (20 mg, 54.7%). LC/MS: rt=2.19min; m/z=403.3 [M+H].

Example 20. Synthesis of Compound SB-1

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added1-(piperazin-1-yl)ethanone (23 mg, 0.18 mmol) and SB (36 mg, 0.09 mmol).The mixture was stirred at rt for 15 h. The residue mixture was pouredin to 5 mL H₂O and extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue mixture was purified with by reverse-phaseprep-HPLC to afford the title compound SB-1 as a white solid (10 mg,25%). LCMS: rt=2.21 min, m/z=445.3 [M+H].

Example 21. Synthesis of Compound SB-2

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added1-methylpiperazine (18 mg, 0.18 mmol) and SB (36 mg, 0.09 mmol). Themixture was stirred at rt for 15 h. The residue mixture was poured in to5 mL H₂O and extracted with EtOAc (2×10 mL). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue mixture was purified with by reverse-phaseprep-HPLC to afford the title compound SB-2 as a white solid (11 mg,29%).

Example 22. Synthesis of Compound SB-3

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was addedpiperidin-3-ol (23 mg, 0.23 mmol) and SB (36 mg, 0.09 mmol). The mixturewas stirred at RT for 15 h. The residue mixture was poured in to 5 mLH₂O and extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue mixture was purified with by reverse-phase prep-HPLC toafford the title compound SB-3 as a white solid and a mixture ofdiasteromers (12 mg, 32%).

Example 23. Synthesis of Compound SB-4

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added4-hydroxypiperidine (18 mg, 0.18 mmol) and compound SB (36 mg, 0.09mmol). After stirring at room temperature for 15 h, the reaction mixturewas poured in to 5 mL H₂O and extracted with EtOAc (2×10 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrate. The reaction mixture was purifiedwith by reverse-phase prep-HPLC to afford SB-4 as a white solid (20 mg,56%).

Example 24. Synthesis of Compound SB-5

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added3-azetidinol (13 mg, 0.18 mmol) and compound SB (36 mg, 0.09 mmol).After stirring at room temperature for 15 h, the reaction mixture waspoured in to 5 mL H₂O and extracted with EtOAc (2×10 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrate. The reaction mixture was purified with byreverse-phase prep-HPLC to afford SB-5 as a white solid (20 mg, 56%).

Example 25. Synthesis of Compound SB-6

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was added3-pyrrolidinol (16 mg, 0.18 mmol) and compound SB (36 mg, 0.09 mmol).After stirring at room temperature for 15 h, the reaction mixture waspoured in to 5 mL H₂O and extracted with EtOAc (2×10 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrate. The reaction mixture was purified with byreverse-phase prep-HPLC to afford SB-6 as a white solid and mixture ofdiasteromers (18 mg, 51%).

Example 26. Synthesis of Compound SB-7

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was addedpiperazine (20 mg, 0.23 mmol) and SB (36 mg, 0.09 mmol). The mixture wasstirred at rt for 15 h. The residue mixture was poured in to 5 mL H₂Oand extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue mixture was purified with by reverse-phase prep-HPLC toafford the SB-7 as a white solid (11 mg, 30%).

Example 28. Synthesis of SB-FF Compound

Synthesis of Compound SA-K.

To a suspension of SA-A (200 g, 734.81 mmol) was added to 300 mL acetylchloride and 300 mL acetic anhydride. The reaction mixture was heated to120° C. for 5 h. After the TLC showed that the starting material wasconsumed completely, then the mixture was filtered and concentrated togive SA-K (204 g, Y: 88.36%). ¹H NMR (004-2): (400 MHz, CDCl3) δ 5.78(d, 1H, J=2.0 Hz), 5.54-5.47 (m, 1H), 2.52-2.41 (m, 2H), 2.30-2.17 (m,3H), 2.15-2.13 (m, 3H), 2.12-1.74 (m, 7H), 1.67-1.48 (m, 3H), 1.38-1.23(m, 4H), 11.03-0.94 (m, 1H), 0.90 (s, 3H).

Synthesis of Compound SB-KK.

To a solution of SA-K (68 g, 216.27 mmol) in 600 mL CH₃CN, was addedselect flour (90.22 g, 324.4 mmol) in portions at −4° C. The resultingreaction mixture was stirred at −4° C. for 3 h. After the TLC showed thereaction was completed, then the mixture was filtered and concentrated.The product was purified by column chromatograph on silica gel elutedwith (Petroleum ether/ethyl acetate20:1-15:1-10:1-8:1-6:1-5:1) to affordSB-KK (26.3 g, 41.8% yield) as a white solid. ¹H NMR (SB-KK) (400 MHz,CDCl₃), δ (ppm), 6.02-5.94 (m, 1H,), 5.20-5.01 (m, 1H), 2.55-2.26 (m,6H), 2.16-2.05 (m 1H), 2.01-1.83 (m, 4H), 1.48-1.22 (m, 5H), 0.98-0.78(m, 61H).

Synthesis of Compound SB-X.

To a solution of SB-KK (27 g, 92.98 mmol) in EtOAc (350 mL) at 20° C.,then Pd/C (2.7 g, 5%) was added in the mixture. The solution was stirredat 20° C., 1 atm for 10 h under hydrogen. After the LCMS showed thereaction was completed, and then the mixture was filtered andconcentrated. The product was purified by column chromatograph on silicagel eluted with (Petroleum ether/ethylacetate40:1-35:1-30:1-25:1-20:1-15:1-10:1-6:1) to give SB-X (15.6 g,56.38%) as a white solid. ¹H NMR (SB-X) (400 MHz, CDCl₃), δ(ppm)=4.68-4.56 (m, 1H), 2.64-2.51 (m, 1H), 2.53-2.03 (m, 8H), 1.97-1.80(m, 4H), 1.49-1.20 (m, 6H), 0.96-0.92 (m, 2H), 0.88-0.78 (m, 1H).

Synthesis of Compound SB-Y.

To a solution of SB-X (47 g, 160.75 mmol) in MeOH (600 mL) at 23° C.,then 2.35 g of TsOH was added in the mixture. The solution was stirredat 60° C. for 1.5 h. After the TLC showed the reaction was completed,and then the mixture was filtered and concentrated to give SB-Y (35 g,64.33%) as a white solid. ¹H NMR (SB-Y) (400 MHz, CDCl₃), δ(ppm)=4.74-4.57 (m, 1H), 3.16 (s, 3H), 3.10 (s, 3H), 2.47-2.35 (m, 1H),2.15-2.09 (m, 1H), 2.06-1.82 (m, 6H), 1.77-1.15 (m, 11H), 1.05-0.96 (m,1H), 0.89 (s, 3H), 0.83-0.77 (m, 1H).

Synthesis of Compound SB-Z.

To a solution of ethyltriphenylphosphonium bromide (115.17 g, 310.23mmol) in 150 mL THF, was added KOt-Bu (34.81 g, 310.23 mmol). Thereaction mixture was heated to 60° C. for 1 h and SB-Y (35 g, 103.41mmol) was added to the mixture which was stirred at 60° C. for anadditional 15 h. The reaction mixture was cooled and extracted 1500 mLEtOAc, washed with brine and concentrated to afford SB-Z as a whitesolid (120 g, crude). ¹H NMR (SB-Z) (400 MHz, CDCl₃), δ (ppm)=5.13-5.07(m, 1H), 4.67-4.54 (m, 1H), 3.14 (s, 3H), 3.09 (s, 3H), 2.42-2.15 (m,3H), 1.92-1.79 (m, 3H), 1.67-1.61 (m, 4H), 1.57-1.50 (m, 2H), 1.45-1.15(min, 101-1), 1.01-0.94 (m, 1H), 0.92 (s, 3H), 0.90-0.84 (m, 1H).

Synthesis of Compound SB-AA.

To a solution of SB-Z (120 g, crude) in 600 mL THF, was added 2M aqueousHCl 90 mL. the reaction mixture was stirred at 22° C. for 1 h. After theTLC showed the reaction was completed, then the reaction was quenchedwith aq.NaHCO₃. The reaction was extracted with 500 mL EtOAc, washedwith brine and evaporated in vacuo. The resulting residue was purifiedby chromatography (petroleum ether/ethylacetate=150:1-125:1-100:1-80:1-60:1-50:1) to afford SB-AA as a whitesolid (24 g, 76.23% yield). ¹H NMR (SB-AA) (400 MHz, CDCl₃), δ(ppm)=5.13 (m, 1H), 4.65-4.48 (m, 1H), 2.62-2.42 (m, 1H), 2.44-2.07 (m,8H), 1.92-1.80 (m, 1H), 1.72-1.55 (m, 8H), 1.36-1.08 (m, 6H), 0.92 (s,3H), 0.83-0.73 (m, 1H).

Synthesis of Compound SB-BB.

To a solution of Me₃SOI (78.07 g, 354.75 mmol) in 50 mL THF, was added asolution of t-BuOK (39.81 g, 354.75 mmol) in 50 mL THF. The reactionmixture was stirred at 60° C. for 1.5 h. Then a solution of SB-AA (24 g,78.83 mmol) in THF (300 mL) was added in the reaction. The reaction wasstirred for 2.5 h at 23° C. After the TLC showed the reaction wascompleted, then the reaction was quenched with ice water. The reactionwas extracted with 500 mL EtOAc, washed with brine and evaporated invacuo to afford SB-BB as crude product (50 g). ¹H NMR (SB-BB) (400 MHz,CDCl₃), δ (ppm)=5.20-5.11 (m, 1H), 4.65-4.52 (m, 1H), 2.74-2.68 (m, 2H),2.48-1.81 (m, 9H), 1.72-1.64 (m, 4H), 1.55-1.06 (m, 10H), 0.97-0.89 (m,3H), 0.85-0.77 (m, 1H).

Synthesis of Compound SB-CC.

To a solution of SB-BB (50 g, crude) in 300 mL THF, was added LiAlH₄(8.99 g, 236.49 mmol) at 0° C. the reaction mixture was stirred at 23°C. for 1.5 h. After the TLC showed the reaction was completed, then thereaction was quenched with water. The reaction was extracted with 1000mL EtOAc, washed with brine and evaporated in vacuo. The resultingresidue was purified by chromatography (petroleum ether/ethylacetate=100:1-80:1-60:1-50:1-40:1-30:1) to afford SB-CC as a white solid(19 g, 75.19% yield). ¹H NMR (SB-CC) (400 MHz, CDCl₃), δ (ppm)=5.17-5.07(m, 1H), 4.66-4.48 (m, 1H), 2.41-2.32 (m, 1H), 2.28-2.15 (m, 2H),2.09-2.05 (m, 1H), 1.88-1.75 (m, 2H), 1.68-1.64 (m, 3H), 1.40-1.31 (m,1H), 1.25-1.13 (m, 91-1), 0.89 (s, 31), 0.81-0.72 (m, 1H).

Synthesis of Compound SB-DD.

To a solution of SB-CC (19 g, 59.29 mmol) in dry THF (500 mL) was addedC₂H₉BS (59.29 mL; 10 M solution in THF) at 0° C. After stirring at roomtemperature for 2 hour, the reaction mixture was cooled in an ice baththen quenched slowly with 3M aqueous NaOH (160 mL) followed by 30%aqueous solution of H₂O₂ (100 mL). After stirring at 20° C. for 1.5 h,the mixture filtered and extracted with EtOAc (300 mL). The combinedorganic layers was treated with aq.Na₂S₂O₃, extracted, dried andconcentrated to afford SB-DD as the crude (21 g, crude). The crudeproduct was used in the next step without further purification.

Synthesis of Compound SB-EE.

To a solution of SB-DD (21 g, 59.29 mmol) in 200 mL CH₂Cl₂, was addedPCC (25.56 g, 118.58 mmol) at 0° C., stirred at 22° C. for 2 h. Thereaction mixture was filtered and extracted with 20 mL CH₂Cl₂, washedwith aq.NaHCO₃, aq.Na₂S₂O₃, brine and evaporated in vacuo. The residuewas purified by chromatography (petroleum ether/ethylacetate=15:1-10:1-6:1) to afford SB-EE as a white solid (12 g, 60.15%yield). ¹H NMR (SB-EE) (400 MHz, CDCl₃), δ (ppm)=4.65-4.46 (m, 1H),2.55-2.51 (m, 1H), 2.22-2.09 (m, 4H), 2.06-1.97 (m, 32H), 1.88-1.77 (m,2H), 1.69-1.54 (m, 5H), 1.48-1.30 (m, 3H), 1.28-1.05 (m, 11H), 0.83-0.72(m, 1H), 0.63 (s, 31).

Synthesis of Compound SB-FF.

To a solution of SB-EE (12 g, 35.66 mmol) in 1500 mL MeOH, was added HBr(5 drops) and Br₂ (2.01 mL, 39.23 mmol) at 0° C. The reaction wasstirred at 16° C. for 2 h. The reaction mixture was quenched withaq.NaHCO₃ and concentrated. Then the mixture was extracted with 1000 mlEtOAc, washed with brine and evaporated in vacuo. The product waspurified by column chromatograph on silica gel eluted with (petroleumether/ethyl acetate=12:1-10:1-8:1-6:1-3:1) to afford SB-FF as a whitesolid (12.3 g, 83.03% yield). ¹H NMR (SB-FF) (400 MHz, CDCl₃), δ(ppm)=4.64-4.47 (m, 1H), 3.95-3.86 (m, 2H), 2.89-2.80 (m, 1H), 2.23-2.16(m, 1H), 2.07-1.64 (m, 8H) 1.46-1.06 (m, 14H), 0.83-0.74 (m, 1H), 0.67(s, 3H).

Example 29. Synthesis of Compound SF-13

To a suspension of SF-12 (40 mg, 0.09 mmol) in THF (5 mL) was addedmorpholine (40 mg, 0.50 mmol) and K₂CO₃ (60 mg, 0.45 mmol). The mixturewas stirred at 25° C. for 15 h. The solution was then diluted with ethylacetate (100 mL) and the resulting solution was washed with brine (100mL), dried over sodium sulfate and concentrated in vacuo. The reactionmixture was purified with by reverse-phase prep-HPLC to afford SF-13 asa white solid (8 mg, 20% yield).

Example 30. Synthesis of Compound SF-14

To a suspension of SF-12 (40 mg, 0.09 mmol) in THF (5 mL) was added1-(piperazin-1-yl)ethanone (60 mg, 0.50 mmol) and K₂CO₃ (60 mg, 0.45mmol). The mixture was stirred at 25° C. for 15 h. The solution was thendiluted with ethyl acetate (100 mL) and the resulting solution waswashed with brine (100 mL), dried over sodium sulfate and concentratedin vacuo. The reaction mixture was purified with by reverse-phaseprep-HPLC to afford SF-14 as a white solid (15 mg, 38% yield).

Example 31. Synthesis of Intermediate SI-6

Synthesis of Compound SI-1 and SI-2.

To a solution of compound SB-F (1.3 g, 4.5 mmol) and PhSO₂CH₂F (790 mg,4.5 mmol) in THF (25 mL) and HMPA (0.5 mL) at −78° C. under N₂ was addedLHMDS (5.5 mL, 1M in THF) dropwise. After stirring at −78° C. for 2 h,the reaction mixture was quenched with saturated aqueous NH₄Cl solution(10 mL) and allowed to warm to room temperature then extracted with Et₂O(20 mL×3). The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrate. The residue was purifiedby silica gel column chromatography (petroleum ether/ethyl acetate=10/1)to give the mixture of compound SI-1 and SI-2 (1.53 g). The mixture wasfurther purified by chiral-HPLC to afford compound SI-1 (220 mg, t=3.41min).

Synthesis of Compound SI-3.

To a solution of compound SI-1 (200 mg, 0.434 mmol) and anhydrousNa₂HPO₄ (100 mg) in anhydrous methanol (15 mL) at −20° C. under N₂ wasadded Na/Hg amalgam (400 mg). After stirring at −20° C. to 0° C. for 1h, the methanol solution was decanted out and the solid residue waswashed with Et₂O (5×3 mL). The solvent of combined organic phase wasremoved under vacuum, and 20 ml brine was added, followed by extractingwith Et₂O. The combined ether phase was dried with MgSO₄, and the etherwas removed to give the crude product, which was further purified bysilica gel chromatography (petroleum ether/ethyl acetate=10/1) to giveproduct 99 mg, 69%.

Synthesis of Compound SI-4.

To a solution of compound SI-3 (95 mg, 0.296 mmol) in dry THF (5 mL) wasadded borane-tetrahydrofuran complex (1 mL of 1.0 M solution in THF).After stirring at room temperature for 1 hour, the reaction mixture wascooled in an ice bath then quenched slowly with 10% aqueous NaOH (1 mL)followed by 30% aqueous solution of H₂O₂ (1.2 mL). The mixture wasallowed to stir at room temperature for 1 hour then extracted with EtOAc(3×10 mL). The combined organic layers were washed with 10% aqueousNa₂S₂O₃ (10 mL), brine (10 mL), dried over MgSO₄, filtered andconcentrated to afford compound SI-4 (120 mg crude). The crude productwas used in the next step without further purification.

Synthesis of Compound SI-5.

To a solution of compound SI-4 (120 mg crude) was dissolved in 10 mL ofwet dichloromethane (dichloromethane had been shaken with severalmilliliters of H₂O then separated from the water layer) was addedDess-Martin periodinate (300 mg, 707 mmol). After stirring at roomtemperature for 24 h, the reaction mixture was extracted withdichloromethane (3×10 mL). The combined organic layers were washed with10% aqueous Na₂S₂O₃ (10 mL), brine (10 mL), dried over MgSO₄, filteredand concentrated. The residue was purified by chromatography on silicagel (petroleum ether/ethyl acetate=1:5) to afford compound SI-5 (70 mg,70% for two steps) as a white solid.

Synthesis of Compound SI-6.

To a solution of reactant (200 mg, 0.594 mmol) in methanol (5 mL) wasadded 48% hydrobromic acid (300 mg, 1.782 mmol) followed by bromine (475mg, 0.152 mL, 2.97 mmol). The solution was heated at 25° C. for 2 hours.Then the mixture was poured into cooled water (50 mL). The resultingsolid was extracted with ethyl acetate (2×100 mL). The combined organicextracts were washed with brine (100 mL), dried over magnesium sulfateand concentrated in vacuo. The crude product was used directly withoutfurther purification in the next step.

Example 32. Synthesis of Compound SI-7

To a suspension of K₂CO₃ (19 mg, 0.14 mmol) in THF (5 mL) was addedmorpholine (12 mg, 0.14 mmol) and compound SI-6 (30 mg, 0.07 mmol).After stirring at room temperature for 15 h, the reaction mixture waspoured into 5 mL H₂O and extracted with EtOAc (2×10 mL). The combinedorganic layers were washed with brine (2×10 mL), dried over sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by reverse-phase prep-HPLC to afford SI-7 as a white solid (6mg, 21%). LCMS: Rt=2.24 min. m/z=422.2 [M+H]⁺.

Example 33. Synthesis of Compound SI-8

To a suspension of K₂CO₃ (19 mg, 0.14 mmol) in THF (5 mL) was added1-(methylsulfonyl) piperazine (23 mg, 0.14 mmol) and compound SI-6 (30mg, 0.07 mmol). After stirring at room temperature for 15 h, thereaction mixture was poured into 5 mL H₂O and extracted with EtOAc (2×10mL). The combined organic layers were washed with brine (2×10 mL), driedover sodium sulfate, filtered and concentrated under vacuum. The residuewas purified by reverse-phase prep-HPLC to afford SI-8 as a white solid(3 mg, 10%). LCMS: Rt=2.20 min. m/z=499.4 [M+H]⁺.

Example 34. Synthesis of Intermediate SJ-10

Synthesis of Compound SJ-7.

A mixture of reactant mixture SA-J-1 and SA-J-2 (3.0 g, 10.0 mmol, 1:1)was added dry (Bu)₄NF, then the mixture was heated 100° C. overnight.The residual mixture was poured in to 50 mL H₂O and extracted with EtOAc(2×50 mL). The combined organic layers were washed with brine solution,dried over sodium sulfate, filtered and concentrated. The residue waspurified by flash chromatography (eluant: petroleum ether/ethylacetate=20:1) to afford product mixture SJ-7-1 and SJ-7-2 (2.1 g, 6.5mmol, 65%) as a white solid.

Synthesis of Compound SJ-8.

To a solution of reactant mixture SJ-7-1 and SJ-7-2 (2.1 g, 6.5 mmol) inanhydrous THF (30 mL) was added BH₃.THF (1.0 M, 13.0 mL, 13.0 mmol), thesolution was stirred at 25° C. overnight. Then the reaction was quenchedby addition of water (5 mL). 2 M NaOH solution (20 mL) was addedfollowed by 30% H₂O₂ (20 mL). The mixture was stirred at roomtemperature for 1 hour. The mixture was diluted with ethyl acetate (200mL) and resulting solution was washed with brine (2×100 mL), dried overmagnesium sulfate and concentrated in vacuo. The crude product mixturewas used directly in the next step without further purification.

Synthesis of Compound SJ-9.

To a solution of crude reactant mixture SJ-8-1 and SJ-8-2 (2.2 g, 6.5mmol, theoretical amount) in dichloromethane (40 mL) was addedPyridinium chlorochromate (Pcc) in portions (2.8 g, 13.0 mmol). Thesolution was stirred at 25° C. overnight. Then the mixture was filteredthrough a short pad of silica gel and the silica gel was washed withdichloromethane (3×50 mL). All filtrate was combined and concentrated invacuo. The residue was purified by flash chromatography (eluant:petroleum ether/ethyl acetate=15:1) to afford product SJ-9-1 (910 mg,2.7 mmol, Yield=41% (2 steps)) as a white solid and product SJ-9-2 (850mg, 2.5 mmol, Yield=39% (2 steps)) as a white solid.

Synthesis of Compound SJ-10.

To a solution of reactant SJ-9-2 (100 mg, 0.301 mmol) in methanol (10mL) was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed bybromine (241 mg, 0.077 mL, 1.505 mmol). The solution was heated at 25°C. for 1.5 hours. Then the mixture was poured into cooled water (50 mL).The resulting solid was extracted with ethyl acetate (2×50 mL). Thecombined organic extracts were washed with brine (50 mL), dried overmagnesium sulfate and concentrated in vacuo. The crude product SJ-10 wasused directly without further purification in the next step.

Example 35. Synthesis of Compound SJ-11

To a solution of crude reactant SJ-10 (62 mg, 0.150 mmol) in anhydrousTHF (5 mL) was added morpholine (65.3 mg, 0.75 mmol) followed bypotassium carbonate (104 mg, 0.75 mmol). The solution was heated at 25°C. overnight. Then the solution was diluted with ethyl acetate (100 mL).The resulting solution was washed with brine (2×50 mL), dried overmagnesium sulfate and concentrated in vacuo. The crude product waspurified by reverse phase prep-HPLC to afford product SJ-11 (14 mg,0.033 mmol, Yield=22%) as a white solid. LC-MS: rt=2.19 min, m/z=422.2[M+H]⁺

Example 36. Synthesis of Compound SJ-12

To a suspension of K₂CO₃ (55 mg, 0.4 mmol) in THF (5 mL) was added1-(methylsulfonyl)piperazine (66 mg, 0.4 mmol) and Compound SJ-10 (83mg, 0.2 mmol). The mixture was stirred at RT for 15 h then the residuemixture was poured into 5 mL H₂O and extracted with EtOAc (2×10 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue mixture was purified byreverse-phase prep-HPLC to afford SJ-12 as a white solid (10 mg, 10%).LC-MS: rt=2.09 min, m/z=499.3 [M+H]⁺

Example 37. Synthesis of Intermediate SK-11

Synthesis of Compound SK-2.

To NH₃ (liquid, 2.0 L) was added lithium (7.0 g, 1 mol) at −78° C. Afterthe liquid was turned to deep blue, a solution of compound SK-1 (27.0 g,100 mmol) in t-BuOH (7.4 g, 100 mmol) and THF (20 mL) was addeddropwise. The mixture was stirred at −78° C. for 4 hours. Then NH₄Clsolid (50 g) was added to quench the reaction. The mixture was turnedfrom deep blue to white. The mixture was allowed to warm to roomtemperature and ammonia was evaporated overnight. The residue wasdissolved in 0.5 N aqueous HCl (50 mL) and extracted withdichloromethane (200 mL×3). The combined organic layers were washed withsaturated NaHCO₃ (200 mL) and brine (200 mL), dried over magnesiumsulfate and concentrated in vacuo. The crude product was purified byflash chromatography (PE/EtOAc=4:1) to get product SK-2 (18.98 g, 68.7%)as a white solid.

Synthesis of Compound SK-3.

A sample of 19.0 g compound SK-2 (68.84 mmol) was dissolved in 50 mL THFat 0° C. Then 70 mL MeMgBr in THF (3M) was added dropwise in 30 min. Thereaction was kept at 0° C. for 8 h. The reaction mixture was quenchedwith ice-cold water and extracted with EtOAc (200 mL×3). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated. The white residue was purified by flashcolumn chromatography (PE/EtOAc=5:1) to give product SK-3 (19.0 g, 94%)as a white solid.

Synthesis of Compound SK-4.

To a solution of compound SK-3 (19.0 g, 65.07 mmol) in dichloromethane(100 mL) was added pyridinium dichromate (PDC) (48.9 g, 130.14 mmol).The mixture was stirred at room temperature overnight. The solution wasfiltered through a short pad of celite. The celite was washed withCH₂Cl₂ (3×100 mL). The combined CH₂Cl₂ solution was concentrated invacuo. The residue was purified by flash chromatography (eluant:PE/EtOAc=5:1) to afford product SK-4 (10.0 g, 53%) as a white solid.

Synthesis of Compound SK-5.

To a solution of compound SK-4 (5.0 g, 17.2 mmol) in anhydrous toluene(100 mL) was added to the p-toluenesulfonic acid on silica gel (80 g),the mixture was stirred under 45° C. for 1 hour. The insolublebi-products were removed from silica gel by elution with PE/EtOAc(10/1). The crude product SK-5 (3.20 g, 11.75 mmol) was used in the nextstep without further purification.

Synthesis of Compound SK-6.

To a solution of compound SK-5 (3.20 g, 11.75 mmol) in 10 mL anhydrousdichloromethane was added mCPBA (4.04 g, 23.50 mmol), and the reactionmixture was stirred over night at room temperature. The reaction mixturethen was extracted with CH₂Cl₂, the combined organic layer was washedtwice with NaHCO₃ (100 mL) and brine, dried over Na₂SO₄ andconcentrated. The crude product SK-6 was used in the next step withoutfurther purification.

Synthesis of Compound SK-7.

To a solution of compound SK-6 (11.75 mmol) in methanol was added H₂SO₄(0.5 mL), and the reaction mixture was stirred for 2 h at roomtemperature. The reaction solution was then extracted with CH₂Cl₂ (200mL×3), the combined organic layer was washed with NaHCO₃ (100 mL) andbrine, dried over Na₂SO₄ and concentrated. The residue was purified bychromatography (PE/EtOAc=10:1) to afford compound SK-7 (3.30 g, 10.30mmol, Yield=87% for two steps) as a white solid.

Synthesis of Compound SK-8.

To a solution of ethyltriphenylphosphonium bromide (11.52 g, 31.0 mmol)in anhydrous THF (20 mL) was added t-BuOK (3.48 g, 31.0 mmol). Thesolution was turned to reddish and heated at 70° C. for 3 hours. Thencompound SK-7 (3.30 g, 10.30 mmol) was added in one portion. Thereaction solution was heated at 70° C. overnight, then was quenched bythe addition of water (10 mL). The mixture was diluted with EtOAc (200mL) and the resulting solution was washed with brine (2×100 mL), driedover magnesium sulfate and concentrated in vacuo. The crude product SK-8(1.90 g) was used directly in the next step without furtherpurification.

Synthesis of Compound SK-9.

To a solution of compound SK-8 (1.90 g, 5.72 mmol) in dry THF (20 mL)was added BH₃-THF (18 mL of 1.0M solution in THF). After stirring atroom temperature for 1 h, the reaction mixture was cooled in an ice baththen quenched slowly with 10% aqueous NaOH (12 mL) followed by 30% H₂O₂(20 mL). The mixture was allowed to stir at room temperature for 1 hthen extracted with EA (100 mL×3). The combined organic layer was washedwith 10% aqueous Na₂S₂O₃ (50 mL), brine, dried over Na₂SO₄, filtered andconcentrated to afford crude compound SK-9 (1.86 g, 5.31 mmol). Thecrude product was used in the next step without further purification.

Synthesis of Compound SK-10.

To a solution of crude compound SK-9 (1.86 g, 5.31 mmol) indichloromethane (50 mL) was added pyridinium dichromate (PDC) inportions (3.98 g, 10.62 mmol). The solution was stirred at 25° C.overnight. Then the mixture was filtered through a short pad of silicagel and the silica gel was washed with dichloromethane (3×50 mL). Allfiltrate was combined and concentrated in vacuo. The residue waspurified by flash chromatography (eluant: PE/EtOAc=10:1) to affordproduct SK-10 (1.20 g, 3.45 mmol, 65%) as a white solid.

Synthesis of Compound SK-11.

To a solution of reactant SK-10 (100 mg, 0.287 mmol) in methanol (10 mL)was added 48% HBr (152 mg, 0.903 mmol) followed by bromine (0.08 mL,1.505 mmol). The solution was heated at 25° C. for 1.5 hours. Then themixture was poured into cooled water (50 mL). The resulting solid wasextracted with ethyl acetate (2×50 mL). The combined organic extractswere washed with brine (50 mL), dried over magnesium sulfate andconcentrated in vacuo. The crude product SK-11 was used directly withoutfurther purification in the next step.

Example 38. Synthesis of Compound SK-12

To a solution of compound SK-II (60 mg, crude) in dry THF (2 mL) wasadded potassium carbonate (100 mg) and morpholine (100 mg). The reactionmixture was stirred at ambient temperature for 16 hour, and thenextracted with EtOAc (3×10 mL). The combined EtOAc extracts were washedwith brine (10 mL), dried over MgSO₄, filtered, and concentrated. Theresidue was purified by preparative HPLC to afford title compound SK-12(17 mg, 27%) as a white solid.

Example 39. Synthesis of Intermediate SL-11

Synthesis of Compound SL-2.

To NH₃ (liquid, 2.0 L) was added lithium (7.0 g, 1 mol) at −78° C. Afterthe liquid turned to a deep blue, a solution of reactant SL-1 (27.0 g,100 mmol) in t-BuOH (7.4 g, 100 mmol) and THF (20 mL) was addeddropwise. The mixture was stirred at −78° C. for 4 hours, then NH₄Clsolid (50 g) was added to quench the reaction. The mixture then turnedfrom deep blue to white. The mixture was allowed to warm to roomtemperature and ammonia was evaporated in a fume hood overnight. Theresidue was dissolved in 0.5 N HCl (50 mL) and extracted withdichloromethane (200 mL×3). The combined organic layers were washed withsaturated NaHCO₃ (200 mL) and brine (200 mL), dried over magnesiumsulfate and concentrated in vacuo. The crude product was purified byflash chromatography (petroleum ether/ethyl acetate=4:1) to get productSL-2 (18.98 g, 68.76 mmol, Yield=68.7%) as a white solid.

Synthesis of Compound SL-3.

19.0 g of compound SL-2 (68.84 mmol) was dissolved in 50 mL THF at 0° C.Then 70 mL MeMgBr in THF (3M) was added dropwise over 30 minutes thenthe reaction was kept at 0° C. for 8 h. The reaction mixture wasquenched with ice-cold water and extracted with EA (200 mL×3). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated. The white residue was purified byflash column chromatography (petroleum ether/ethyl acetate=5:1) to getproduct SL-3 (19.0 g, 65.07 mmol Yield=94%) as a white solid.

Synthesis of Compound SL-4.

To a solution of reactant SL-3 (19.0 g, 65.07 mmol) in dichloromethane(100 mL) was added pyridinium dichromate (PDC) (48.9 g, 130.14 mmol) atroom temperature and the mixture was stirred at room temperatureovernight. The solution was filtered through a short pad of celite. Thecelite was washed with CH₂Cl₂ (3×100 mL). The combined CH₂Cl₂ solutionwas concentrated in vacuo. The residue was purified by flashchromatography (eluant: petroleum ether/ethyl acetate=5:1) to affordproduct SL-4 (10.0 g, 34.48 mmol, Yield=53%) as a white solid.

Synthesis of Compound SL-5.

To a solution of reactant SL-4 (5.0 g, 17.2 mmol) in anhydrous toluene(100 mL) was rapidly added to the p-toluenesulfonic acid on silica gel(80 g), the mixture is stirred at 45° C. for 1 hour. The product wereremoved from silica gel by elution with (petroleum ether/ethylacetate=30:1). The crude product SL-5 (3.20 g, 11.75 mmol) was used inthe next step without further purification.

Synthesis of Compound SL-6.

To a solution of SL-5 (3.20 g, 11.75 mmol) in 10 mL anhydrousdichloromethane was added mCPBA (4.04 g, 23.50 mmol), and the reactionmixture was stirred overnight at room temperature. The solution was thenextracted with CH₂Cl₂ (2×100 mL), and the combined organic layer waswashed twice with NaHCO₃ (100 mL) and brine, dried over Na₂SO₄ andconcentrated. The crude product SL-6 was used in the next step withoutfurther purification.

Synthesis of Compound SL-7.

To a solution of SL-6 (900 mg, 3.12 mmol) in ethanol (50 mL) was addedconcentrated H₂SO₄ (0.5 mL), and the reaction mixture was stirred for 2h at room temperature. As soon as TLC indicated complete conversion, thesolution was extracted with CH₂Cl₂ (200 mL×3), the combined organiclayer was washed with NaHCO₃ (100 mL) and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by chromatography (petroleumether/ethyl acetate=10:1) to afford compound SL-7 (600 mg, 1.80 mmol,Yield=57.6% for two steps) as a white solid.

Synthesis of Compound SL-8.

To a solution of ethyltriphenylphosphonium bromide (1.99 g, 5.96 mmol)in anhydrous THF (10 mL) was added t-BuOK (500 mg, 4.48 mmol). Thesolution was turned to reddish and heated at 70° C. for 3 hours. Thenthe reactant SL-7 (600 mg, 1.79 mmol) was added in one portion. Thesolution was heated at 70° C. overnight. The reaction was quenched bythe addition of water (5 mL). The mixture was diluted with ethyl acetate(100 mL) and the resulting solution was washed with brine (2×50 mL),dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by flash chromatography (eluant: petroleum ether:ethylacetate=20:1) to afford product SL-8 (1.55 g, 4.48 mmol, 75.2%) as awhite solid.

Synthesis of Compound SL-9.

To a solution of compound SL-8 (1.20 g, 3.47 mmol) in dry THF (20 mL)was added BH₃-THF (18 mL of 1.0M solution in THF). After stirring atroom temperature for 1 h, the reaction mixture was cooled in an ice baththen quenched slowly with 10% aqueous NaOH (10 mL) followed by 30% H₂O₂(15 mL). The mixture was allowed to stir at room temperature for 1 hthen extracted with EA (100 mL×3). The combined organic layer was washedwith 10% aqueous Na₂S₂O₃ (50 mL), brine, dried over Na₂SO₄, filtered andconcentrated to afford crude compound SL-9 (1.12 g). The crude productwas used in the next step without further purification.

Synthesis of Compound SL-10.

To a solution of crude reactant SL-9 (1.12 g, 3.08 mmol) indichloromethane (50 mL) was added pyridinium dichromate (PDC) inportions (3.32 g, 6.16 mmol) at room temperature. The solution wasstirred at 25° C. overnight, then the mixture was filtered through ashort pad of silica gel and the silica gel was washed withdichloromethane (3×50 mL). All filtrate was combined and concentrated invacuo. The residue was purified by flash chromatography (eluant:petroleum ether/ethyl acetate=10:1) to afford product SL-10 (0.95 g,2.62 mmol, Yield=85.1%) as a white solid.

Synthesis of Compound SL-11.

To a solution of reactant SL-10 (80 mg, 0.221 mmol) in methanol (5 mL)was added 48% hydrobromic acid (148 mg, 0.884 mmol) followed by bromine(241 mg, 0.077 mL, 1.505 mmol). The solution was heated at 25° C. for1.5 hours, then the mixture was poured into cooled water (50 mL). Theresulting solid was extracted with ethyl acetate (2×50 mL). The combinedorganic extracts were washed with brine (20 mL), dried over magnesiumsulfate and concentrated in vacuo. The crude product SL-11 was useddirectly without further purification in the next step.

Example 40. Synthesis of Compound SL-12

To a solution of compound SL-11 (60 mg, crude) in dry THF (2 mL) wasadded potassium carbonate (100 mg) and morpholine (100 mg). The reactionmixture was stirred at ambient temperature for 16 hour, and thenextracted with EtOAc (3×10 mL). The combined EtOAc extracts were washedwith brine (10 mL), dried over MgSO₄, filtered, and concentrated. Theresidue was purified by preparative HPLC to afford title compound SL-12(14 mg, yield=23%) as a white solid.

Example 50. Synthesis of Intermediates SP-14

Synthesis of Compound SP-2.

To a solution of reactant SP-1 (10.0 g, 36.44 mmol) in pyridine (30 mL)was added acetic anhydride (5.0 mL, 52.89 mmol). The mixture was stirredat 60° C. overnight. Then the solution was poured into ice-water (200mL). The white precipitate was filtered and dissolved in ethyl acetate(300 mL). The resulting solution was washed with sat. CuSO₄.5H₂Osolution (2×200 mL) in order to remove residual pyridine. The organiclayer was further washed with brine (200 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography (eluant: petroleum ether/ethyl acetate=4:1) to affordproduct SP-2 (11.125 g, 35.16 mmol, Yield=96%) as a white solid.

Synthesis of Compound SP-3.

To a solution of reactant SP-2 (4.68 g, 14.79 mmol) in THF (150 mL) wasadded LiHMDS (1.0 M in THF solution, 17.74 mL, 17.74 mmol) at −78° C.The solution was stirred at −78° C. for 30 minutes. Then HMPA (3.09 mL,17.74 mmol) was added. The solution was stirred at −78° C. for another30 minutes. Then iodomethane (2.76 mL, 44.37 mmol) was added. Thesolution was further stirred at −78° C. for 2 hours and warmed to roomtemperature and stirred for 1 hour. The reaction was quenched byaddition of water (10 mL). Most THF solvent was removed in vacuo. Thenthe residue was diluted with ethyl acetate (300 mL) and the resultingsolution was washed with brine (2×200 mL), dried over magnesium sulfate.Removal of solvent in vacuo afforded crude product SP-3 (4.50 g, 13.62mmol, Yield=92%) as thick oil. The crude product was used in the nextstep without further purification.

Synthesis of Compound SP-4 & SP-4a.

To a solution of crude reactant SP-3 (11.62 g, 35.16 mmol, theoreticalamount) in methanol (100 mL) and water (20 mL) was added sodiumhydroxide (2.81 g, 70.32 mmol). The solution was heated at 60° C. for 1hour. Then most methanol solvent was removed in vacuo. The residualsolution was acidified by 2 M HCl to pH 5-6. The aqueous layer wasextracted with ethyl acetate (3×100 mL). The combined organic extractswere washed with brine (200 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by flash chromatography(eluant: petroleum ether/ethyl acetate=5:1) to afford pure product SP-4(2.354 g, 8.162 mmol, Yield=23%) and pure product SP-4a (5.306 g, 18.40mmol, Yield=50%) as a white solid. Compound SP-4: ¹HNMR (500 MHz, CDCl₃)δ (ppm): 5.81 (1H, s), 3.67 (1H, t), 1.11 (d, 3H), 0.81 (3H, s).

Synthesis of Compound SP-5.

To liquid ammonia (200 mL) was added lithium (1.80 g, 260 mmol) at −78°C. The liquid then turned to deep blue. Then a solution of reactant SP-4(3.0 g, 10.40 mmol) in t-BuOH (1.0 mL, 10.40 mmol) and THF (100 mL) wasadded to Li-ammonia solution. The mixture was stirred at −78° C. for 4hours. Then NH₄Cl solid (20 g) was added to quench the reaction. Themixture was turned from deep blue to white. The mixture was allowed towarm to room temperature and ammonia was evaporated in a hood overnight.To the residue was added water (300 mL). The mixture was acidified byconc. HCl to pH 6-7. Then ethyl acetate (300 mL) was added. Theseparated aqueous layer was further extracted with ethyl acetate (2×100mL). The combined organic extracts were washed with brine (300 mL),dried over magnesium sulfate and concentrated in vacuo. The crudeproduct SP-5 was used directly without further purification in the nextstep.

Synthesis of Compound SP-6.

To a solution of crude reactant SP-5 (1.749 g, 6.022 mmol) indichloromethane (60 mL) was added pyridinium dichromate (PDC) (3.398 g,9.033 mmol). The mixture was stirred at room temperature overnight. Thesolution was filtered through a short pad of celite. The celite waswashed with CH₂Cl₂ (3×50 mL). The combined CH₂Cl₂ solution wasconcentrated in vacuo. The residue was purified by flash chromatography(eluant: petroleum ether/ethyl acetate=5:1) to afford product SP-6(1.298 g, 4.50 mmol, Yield=75%) as a white solid.

Synthesis of Compound SP-7.

To a solution of reactant SP-6 (1.948 g, 6.754 mmol) in anhydrousmethanol (50 mL) was added p-toluenesulfonic acid monohydrate (128 mg,0.6754 mmol). The solution was heated at 70° C. for 3 hours. Thereaction was quenched by addition of sat. Na₂CO₃ solution (10 mL). Mostmethanol solvent was removed in vacuo. Then the residue was diluted withethyl acetate (200 mL). The resulting solution was washed with sat.Na₂CO₃ solution (2×100 mL). The combined aqueous layers were extractedwith ethyl acetate (50 mL). The combined organic extracts were washedwith brine (100 mL), dried over magnesium sulfate and concentrated invacuo. The residue was purified by flash chromatography (eluant:petroleum ether/ethyl acetate=10:1, added 0.1% NEt₃) to afford productSP-7 (652 mg, 1.949 mmol, Yield=29%) as a white solid. Furthermore,starting material (1.338 g) was also recovered. So the yield based onrecovered starting material is 92%.

Synthesis of Compound SP-8.

To a solution of ethyltriphenylphosphonium bromide (8.795 g, 23.69 mmol)in anhydrous THF (20 mL) was added t-BuOK (2.658 g, 23.69 mmol). Thesolution then became reddish in color and was heated at 70° C. for 2hours. Then the reactant SP-7 (1.642 g, 4.909 mmol) was added in oneportion. The solution was heated at 70° C. overnight. The reaction wasquenched by the addition of water (10 mL). The mixture was diluted withethyl acetate (200 mL) and the resulting solution was washed with brine(2×100 mL), dried over magnesium sulfate and concentrated in vacuo. Thecrude product SP-8 was used directly in the next step without furtherpurification.

Synthesis of Compound SP-9.

To the crude product SP-8 (1.702 g, 4.909 mmol, theoretical amount) inTHF (30 mL) was added 2 M HCl (3 mL). The solution was stirred atambient temperature for 1 hour. The mixture was diluted with ethylacetate (300 mL) and the resulting solution was washed with sat. Na₂CO₃solution (2×100 mL). The combined aqueous layers were extracted withethyl acetate (100 mL). The combined organic extracts were washed withbrine (100 mL), dried over magnesium sulfate and concentrated in vacuo.The residue was purified by flash chromatography (eluant: petroleumether/ethyl acetate=100:3) to afford crude product 9 (1.746 g) as awhite solid which was contaminated with some inseparated PPh₃. Judged bythe integration of ¹HNMR spectrum, the ratio of desired product to PPh₃is 3:1, so the amount of desired product SP-9 is 1.354 g (4.506 mmol),the yield is 92%.

Synthesis of Compound SP-10.

To a solution of trimethylsulfoxonium iodide (5.213 g, 23.69 mmol) inanhydrous DMSO (30 mL) was added sodium hydride (60% wt, 948 mg, 23.69mmol). The mixture was stirred at 25° C. for 1 hour. Then a solution ofcrude reactant (1.746 g, contaminated with some residual PPh3,theoretical amount, 1.354 g, 4.506 mmol) in anhydrous THF (10 mL) wasadded. The mixture was stirred at 25° C. overnight. The reaction wasquenched by addition of water (5 mL). The mixture was diluted with ethylacetate (300 mL) and the resulting solution was washed with water (2×100mL), followed by brine (100 mL) dried over magnesium sulfate andconcentrated in vacuo. The crude product 10 was used directly in thenext step without further purification.

Synthesis of Compound SP-11.

To a solution of crude reactant SP-10 (theoretical amount, 1.417 g,4.506 mmol) in anhydrous THF (30 mL) was added lithium aluminum hydride(342 mg, 9.012 mmol) in portions. The suspension was stirred at 25° C.for 1 hour. Then the reaction was quenched by addition of ethyl acetate(5 mL) followed by water (5 mL). A white solid was filtered andthoroughly washed with ethyl acetate (5×100 mL). The combined filtratewas washed with brine (200 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by flash chromatography(eluant: petroleum ether/ethyl acetate=20:1) to afford product SP-11(458 mg, 1.447 mmol, 2 steps total yield=32%) as a white solid.

Synthesis of Compound SP-12.

To a solution of reactant SP-11 (458 mg, 1.447 mmol) in anhydrous THF(15 mL) was added BH₃.THF (1.0 M, 7.23 mL, 7.23 mmol), The solution wasstirred at 25° C. overnight. Then the reaction was quenched by additionof water (5 mL). 2 M NaOH solution (10 mL) was added followed by 30%H₂O₂ (10 mL). The mixture was stirred at room temperature for 1 hour.The mixture was diluted with ethyl acetate (200 mL) and resultingsolution was washed with brine (2×100 mL), dried over magnesium sulfateand concentrated in vacuo. The crude product was used directly in thenext step without further purification.

Synthesis of Compound SP-13.

To a solution of crude reactant SP-12 (484 mg, 1.447 mmol, theoreticalamount) in dichloromethane (40 mL) was added pyridinium dichromate (PDC)in portions (1633 mg, 4.341 mmol). The solution was stirred at 25° C.overnight. Then the mixture was filtered through a short pad of silicagel and the silica gel was washed with dichloromethane (3×50 mL). Allfiltrate was combined and concentrated in vacuo. The residue waspurified by flash chromatography (eluant: petroleum ether/ethylacetate=8:1) to afford product SP-13 (305 mg, 0.917 mmol, Yield=63% (2steps)) as a white solid. ¹³CNMR (100 MHz, CDCl3) δ (ppm): 209.75,71.09, 63.96, 55.89, 47.96, 47.80, 47.00, 44.35, 41.19, 40.22, 39.05,37.95, 34.49, 33.14, 31.54, 30.92, 28.46, 25.82, 24.22, 22.76, 15.14,13.45.

Synthesis of Intermediate SP-14.

To a solution of reactant SP-13 (100 mg, 0.301 mmol) in methanol (10 mL)was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed by bromine(241 mg, 0.077 mL, 1.505 mmol). The solution was heated at 25° C. for1.5 hours. Then the mixture was poured into cooled water (50 mL). Theresulting solid was extracted with ethyl acetate (2×50 mL). The combinedorganic extracts were washed with brine (50 mL), dried over magnesiumsulfate and concentrated in vacuo. The crude product SP-14 was useddirectly without further purification in the next step.

Example 51. Synthesis of Compound SP-16

To a solution of crude reactant SP-14 (62 mg, 0.150 mmol) in anhydrousTHF (5 mL) was added morpholine (65.3 mg, 0.75 mmol) followed bypotassium carbonate (104 mg, 0.75 mmol). The solution was heated at 25°C. overnight. Then the solution was diluted with ethyl acetate (100 mL).The resulting solution was washed with brine (2×50 mL), dried overmagnesium sulfate and concentrated in vacuo. The crude product waspurified by reverse phase prep-HPLC to afford product SP-16 (16 mg,0.0383 mmol, Yield=26%) as a white solid.

Example 52. Synthesis of Compound SP-17

To a solution of crude reactant SP-14 (61.9 mg, 0.150 mmol, theoreticalamount) in anhydrous THF (5 mL) was added 1-acetylpiperazine (96 mg,0.75 mmol) followed by potassium carbonate (104 mg, 0.75 mmol). Thesolution was heated at 25° C. overnight. Then the solution was dilutedwith ethyl acetate (100 mL). The resulting solution was washed withbrine (2×50 mL), dried over magnesium sulfate and concentrated in vacuo.The crude product was purified by reverse phase prep-HPLC to affordproduct (16 mg, 0.0349 mmpl, two steps overall yield=23%) as a whitesolid.

Example 53. Synthesis of Compound SP-18

To a solution of crude reactant SP-14 (61.9 mg, 0.150 mmol, theoreticalamount) in anhydrous THF (5 mL) was added 1-methanesulfonylpiperazine(123.2 mg, 0.75 mmol) followed by potassium carbonate (103.7 mg, 0.75mmol). The solution was heated at 25° C. overnight. Then the solutionwas diluted with ethyl acetate (100 mL). The resulting solution waswashed with brine (2×50 mL), dried over magnesium sulfate andconcentrated in vacuo. The crude product was purified by reverse phaseprep-HPLC to afford product SP-18 (31 mg, 0.0627 mmol, Yield=42%) as awhite solid.

Example 54. Synthesis of Intermediate SQ-12

Synthesis of Compound SQ-2.

To a solution of compound SQ-1 (500 mg, 1.82 mmol) in THF (18 mL) wasadded LiHMDS (1.0 M in THF solution, 4.00 mL, 4.00 mmol) at −78° C. Thesolution was stirred at −78° C. for 30 minutes. Then HMPA (0.69 mL, 4.00mmol) was added. The solution was stirred at −78° C. for another 30minutes. Then iodomethane (0.34 mL, 5.46 mmol) was added. The solutionwas further stirred at −78° C. for 2 hours and warmed to roomtemperature and stirred for 1 hour. The reaction was quenched byaddition of water (2 mL). Most THF solvent was removed in vacuo. Thenthe residue was diluted with ethyl acetate (100 mL) and the resultingsolution was washed with brine (2×100 mL), dried over magnesium sulfate.Removal of solvent in vacuo afforded crude product SQ-2 (350 mg, 67%) asthick oil. The crude product was used in the next step without furtherpurification.

Synthesis of Compound SQ-3.

To liquid ammonia (100 mL) was added lithium (687 mg, 99.0 mmol) at −78°C. The liquid was turned to deep blue. Then a solution of reactant SQ-2(950 mg, 3.30 mmol) in t-BuOH (244 mg, 3.30 mmol) and THF (20 mL) wasadded to Li-ammonia solution. The mixture was stirred at −78° C. for 4hours. Then NH₄Cl solid (7 g) was added to quench the reaction. Themixture was turned from deep blue to white. The mixture was allowed towarm to room temperature and ammonia was evaporated in a hood overnight.To the residue was added water (100 mL). The mixture was acidified byconc. HCl to pH 6-7. Then ethyl acetate (100 mL) was added. Theseparated aqueous layer was further extracted with ethyl acetate (2×100mL). The combined organic extracts were washed with brine (200 mL),dried over magnesium sulfate and concentrated in vacuo. The crudeproduct SQ-3 was used directly without further purification in the nextstep.

Synthesis of Compound SQ-4.

To a solution of crude compound SQ-3 (980 mg, 3.40 mmol) indichloromethane (60 mL) was added pyridinium dichromate (PDC) (2.56 g,6.80 mmol). The mixture was stirred at room temperature overnight. Thesolution was filtered through a short pad of celite. The celite waswashed with CH₂Cl₂ (3×50 mL). The combined CH₂Cl₂ solution wasconcentrated in vacuo. The residue was purified by flash chromatography(eluant: petroleum ether/EtOAc=5:1) to afford product SQ-4 (680 mg, 69%)as a white solid.

Synthesis of Compound SQ-5.

To a solution of compound SQ-4 (3.24 g, 11.24 mmol) in anhydrousmethanol (100 mL) was added p-toluenesulfonic acid monohydrate (193 mg,1.12 mmol). The solution was heated at 70° C. for 3 hours. The reactionwas quenched by addition of sat. Na₂CO₃ solution (10 mL). Most methanolsolvent was removed in vacuo. Then the residue was diluted with ethylacetate (200 mL). The resulting solution was washed with saturatedNa₂CO₃ solution (2×100 mL). The combined aqueous layers were extractedwith ethyl acetate (50 mL). The combined organic extracts were washedwith brine (100 mL), dried over magnesium sulfate and concentrated invacuo. The residue was purified by flash chromatography (eluant:petroleum ether/EtOAc=15:1, added 0.1% NEt₃) to afford product SQ-5(1.76 g, 47%) as a white solid. Furthermore, starting compound SQ-4(1.34 g) was also recovered. The yield based on recovered startingmaterial is 93%.

Synthesis of Compound SQ-6.

To a suspension of ethyltriphenylphosphonium bromide (6.67 g, 17.96mmol) in anhydrous THF (25 mL) was added t-BuOK (2.01 g, 17.96 mmol).The solution was turned red in color and was then heated at 70° C. for 2hours. Then compound SQ-5 (2.00 g, 5.99 mmol) was added in one portion.The solution was heated at 70° C. overnight. The reaction was quenchedby the addition of water (10 mL). The mixture was diluted with ethylacetate (200 mL) and the resulting solution was washed with brine (2×100mL), dried over magnesium sulfate and concentrated in vacuo. The crudeproduct SQ-6 was used directly in the next step without furtherpurification.

Synthesis of Compound SQ-7.

To the crude product SQ-6 (2.25 g, 6.50 mmol, theoretical amount) in THF(50 mL) was added 4 M HCl (2 mL). The solution was stirred at ambienttemperature for 1 hour. The mixture was diluted with ethyl acetate (300mL) and the resulting solution was washed with saturated Na₂CO₃ solution(2×100 mL). The combined aqueous layers were extracted with EtOAc (100mL). The combined organic extracts were washed with brine (100 mL),dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by flash chromatography (eluant: petroleum ether/EtOAc=20:1) toafford crude product SQ-7 (2.05 g) as a white solid which wascontaminated with some PPh₃. Judged by the integration of ¹HNMRspectrum, the ratio of desired product to PPh₃ is 100:15, so the amountof desired product SQ-7 is 1.78 g (5.94 mmol), the yield is 91%.

Synthesis of Compound SQ-8.

To a solution of trimethylsulfoxonium iodide (6.53 g, 29.70 mmol) inanhydrous DMSO (30 mL) was added sodium hydride (60% wt, 1.19 mg, 29.70mmol). The mixture was stirred at 25° C. for 1 hour. Then a solution ofcrude compound SQ-7 (2.05 g, contaminated with some PPh₃, theoreticalamount, 1.78 g, 5.94 mmol) in anhydrous THF (10 mL) was added. Themixture was stirred at 25° C. overnight. The reaction was quenched byaddition of water (5 mL). The mixture was diluted with ethyl acetate(300 mL) and the resulting solution was washed with water (2×100 mL),followed by brine (100 mL) dried over magnesium sulfate and concentratedin vacuo. The crude product SQ-8 was used directly in the next stepwithout further purification.

Synthesis of Compound SQ-9.

To a solution of crude reactant SQ-8 (theoretical amount, 1.21 g, 3.85mmol) in anhydrous THF (30 mL) was added lithium aluminum hydride (731mg, 19.25 mmol) in portions. The suspension was stirred at 25° C. for 1hour. Then the reaction was quenched by addition of EtOAc (5 mL)followed by water (5 mL). A white solid was filtered and thoroughlywashed with EtOAc (5×100 mL). The combined filtrate was washed withbrine (200 mL), dried over magnesium sulfate and concentrated in vacuo.The residue was purified by flash chromatography (eluant: petroleumether/ethy acetate=15:1) to afford product SQ-9 (560 mg, 1.78 mmol, 2steps total yield, 30%) as a white solid.

Synthesis of Compound SQ-10.

To a solution of reactant SQ-9 (320 mg, 1.013 mmol) in anhydrous THF (20mL) was added BH₃.THF (1.0 M, 5.07 mL, 5.065 mmol), This solution wasstirred at 25° C. overnight then the reaction was quenched by additionof water (4 mL). 2 M aqueous NaOH solution (8 mL) was added followed by30% H₂O₂ (8 mL). The mixture was stirred at room temperature for 1 hour.The mixture was diluted with EtOAc (200 mL) and resulting solution waswashed with brine (2×100 mL), dried over magnesium sulfate andconcentrated in vacuo. The crude product SQ-10 was used directly in thenext step without further purification.

Synthesis of Compound SQ-11.

To a solution of crude compound SQ-10 (320 mg, 1.013 mmol) indichloromethane (30 mL) was added pyridinium dichromate (PDC) inportions (1.14 mg, 3.039 mmol). The solution was stirred at 25° C.overnight. Then the mixture was filtered through a short pad of silicagel and the silica gel was washed with dichloromethane (3×50 mL). Allfiltrate was combined and concentrated in vacuo. The residue waspurified by flash chromatography (eluant: petroleum ether/EtOAc=6:1) toafford product SQ-11 (140 mg, 0.422 mmol, yield 42%, 2 steps) as a whitesolid. ¹³CNMR (100 MHz, CDCl3) δ (ppm): 209.79, 71.09, 63.94, 55.87,47.94, 47.78, 46.97, 44.35, 41.16, 40.20, 39.04, 37.93, 34.48, 33.13,31.55, 30.91, 28.45, 25.80, 24.20, 22.73, 15.15, 13.43.

Synthesis of Intermediate SQ-12.

To a solution of compound SQ-11 (100 mg, 0.301 mmol) in methanol (10 mL)was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed by bromine(241 mg, 0.077 mL, 1.505 mmol). The solution was heated at 25° C. for 2hours. Then the mixture was poured into cooled water (50 mL). Theresulting solid was extracted with ethyl acetate (2×50 mL). The combinedorganic extracts were washed with brine (50 mL), dried over magnesiumsulfate and concentrated in vacuo. The crude product SQ-12 was useddirectly without further purification in the next step.

Example 55. Synthesis of Compound SQ-13

To a solution of crude compound SQ-12 (60 mg, 0.145 mmol) in anhydrousTHF (5 mL) was added morpholine (63.2 mg, 0.726 mmol) followed bypotassium carbonate (101 mg, 0.75 mmol). The solution was heated at 25°C. overnight. Then the solution was diluted with EtOAc (100 mL). Theresulting solution was washed with brine (2×50 mL), dried over magnesiumsulfate and concentrated in vacuo. The crude product was purified byreverse phase prep-HPLC to afford product SQ-13 (8 mg, 13%) as a whitesolid.

Example 56. Synthesis of Compound SQ-14

To a solution of crude compound SQ-12 (50 mg, 0.121 mmol) in anhydrousTHF (5 mL) was added 1-acetylpiperazine (46.5 mg, 0.36 mmol) followed bypotassium carbonate (50.2 mg, 0.36 mmol). The solution was heated at 25°C. overnight. Then the solution was diluted with EtOAc (100 mL). Theresulting solution was washed with brine (2×50 mL), dried over magnesiumsulfate and concentrated in vacuo. The crude product was purified byreverse phase prep-HPLC to afford product SQ-14 (10 mg, 18%) as a whitesolid.

Example 57. Synthesis of Intermediate SR-10

Synthesis of Compound SR-7a and SR-7b.

Compound mixture SA-J-1 and SA-J-2 (5.0 g, 16.7 mmol) was dissolved indry methanol (250 mL), and Na metal (1.2 g, 50.0 mmol) was added and thesolution was refluxed for 16 h. Methanol was then evaporated off and theresidue was dissolved in dichloromethane and washed with H₂O (3×50 mL)and brine (100 mL), dried over MgSO₄, filtered, and concentrated. Thecrude target compound was purified by via silica gel chromatography(petroleum ether/ethyl acetate=10:1 to 5:1), and concentrated to givethe product mixture SR-7a and SR-7b (4.6 g, 83%) as a white solid.

Synthesis of Compound SR-8a and SR-8b.

To a solution of reactant mixture SR-7a and SR-7b (4.6 g, 13.9 mmol) inanhydrous THF (30 mL) was added BH₃.THF (1.0 M, 27.7 mL, 27.7 mmol), thesolution was stirred at 25° C. overnight, then the reaction was quenchedby addition of water (5 mL). 2 M NaOH solution (30 mL) was addedfollowed by 30% H₂O₂ (30 mL). The mixture was stirred at roomtemperature for 1 hour. The mixture was diluted with ethyl acetate (200mL) and resulting solution was washed with brine (2×100 mL), dried overmagnesium sulfate and concentrated in vacuo. The crude product mixturewas used directly in the next step without further purification.

Synthesis of Compound SR-9a and SR-9b.

To a solution of crude reactant mixture SR-8a and SR-8b (4.9 g, 13.9mmol, theoretical amount) in dichloromethane (40 mL) was addedPyridinium chlorochromate (PCC) in portions (6.0 g, 27.8 mmol). Thesolution was stirred at 25° C. overnight then the mixture was filteredthrough a short pad of silica gel and the silica gel was washed withdichloromethane (3×50 mL). All filtrates were combined and concentratedin vacuo. The residue was purified by flash chromatography (eluant:petroleum ether/ethyl acetate=15:1) to afford product SR-9a (2.1 g, 6.03mmol, Yield=43% (2 steps)) as a white solid and product SR-9b (2.2 g,6.32 mmol, Yield=45% (2 steps)) as a white solid.

Synthesis of Intermediate SR-10.

To a solution of reactant SR-9b (100 mg, 0.301 mmol) in methanol (10 mL)was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed by bromine(241 mg, 0.077 mL, 1.51 mmol). The solution was heated at 25° C. for 1.5hours then the mixture was poured into cold water (50 mL) and theresulting solid was extracted with ethyl acetate (2×50 mL). The combinedorganic extracts were washed with brine (50 mL), dried over magnesiumsulfate and concentrated in vacuo. The crude product SR-10 was useddirectly without further purification in the next step.

Example 58. Synthesis of Compound SR-11

To a suspension of K₂CO₃ (55 mg, 0.4 mmol) in THF (5 mL) was addedmorpholine (28 mg, 0.4 mmol) and Compound SR-10 (85 mg, 0.2 mmol). Themixture was stirred at RT for 15 h then the residue mixture was pouredinto 5 mL H₂O and extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue mixture was purified by reverse-phaseprep-HPLC to afford SR-11 as a white solid (24 mg, 29%). LC-MS: rt=2.24min, m/z=434.3 [M+H]⁺

Example 59. Synthesis of Compound SR-12

To a suspension of K₂CO₃ (55 mg, 0.4 mmol) in THF (5 mL) was added1-(methylsulfonyl)piperazine (66 mg, 0.4 mmol) and Compound SR-10 (85mg, 0.2 mmol). The mixture was stirred at RT for 15 h then the residuemixture was poured into 5 mL H₂O and extracted with EtOAc (2×10 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue mixture was purified byreverse-phase prep-HPLC to afford SR-12 as a white solid (13 mg, 13%).LC-MS: rt=2.21 min, m/z=511.3 [M+H]⁺

Example 60. Synthesis of Intermediate SS-2

To a solution of reactant SS-1 (190 mg, 0.545 mmol) in methanol (15 mL)was added 48% hydrobromic acid (275 mg, 1.635 mmol) followed by bromine(435 mg, 0.139 mL, 2.725 mmol). The solution was heated at 25° C. for1.5 hours. Then the mixture was poured into cooled water (50 mL). Theresulting solution was extracted with ethyl acetate (2×100 mL). Thecombined organic extracts were washed with brine (100 mL), dried overmagnesium sulfate and concentrated in vacuo. The crude product was useddirectly without further purification in the next step.

Example 61. Synthesis of Compound SS-3

To a solution of crude reactant SS-2 (61.1 mg, 0.143 mmol, [theoreticalamount]) in anhydrous THF (5 mL) was added 1-methanesulfonylpiperazine(117 mg, 0.715 mmol) followed by potassium carbonate (99 mg, 0.715mmol). The solution was heated at 25° C. overnight. Then the solutionwas diluted with ethyl acetate (100 mL). The resulting solution waswashed with brine (2×50 mL), dried over magnesium sulfate andconcentrated in vacuo. The crude product was purified by reverse phaseprep-HPLC to afford product SS-3 (24 mg, 0.047 mmol, two steps overallyield=33%) as a white solid. LC-MS: rt=2.21 min, m/z=511.2 [M+H]⁺

Example 62. Synthesis of Compound SS-4

To a solution of crude reactant SS-2 (61.1 mg, 0.143 mmol, [theoreticalamount]) in anhydrous THF (5 mL) was added morpholine (62 mg, 0.715mmol) followed by potassium carbonate (99 mg, 0.715 mmol). The solutionwas heated at 25° C. overnight. Then the solution was diluted with ethylacetate (100 mL). The resulting solution was washed with brine (2×50mL), dried over magnesium sulfate and concentrated in vacuo. The crudeproduct was purified by reverse phase prep-HPLC to afford product SS-4(16 mg, 0.0369 mmol, two steps overall yield=26%) as a white solid.LC-MS: rt=2.29 min, m/z=434.2 [M+H]⁺

Example 63. Synthesis of SA-V Compound

Synthesis of Compound SA-K.

Compound SA-J (10 g, 36.7 mmol) was added to 50 mL acetyl chloride and50 mL acetic anhydride. The reaction mixture was heated to 120° C. for 5h, evaporated in vacuo to afford SA-K as a white solid (10 g, 87%yield).

Synthesis of Compound SA-L.

To a solution of reactant SA-K (10 g, 31.8 mmol) in 200 mL THF and 20 mLH₂O, was added mCPBA (11 g, 63.6 mmol) at 0° C., stirred at rt for 15 h,the reaction mixture was extracted 500 mL EtOAc, washed with 100 mLsaturated Na₂SO₃, 100 mL saturated NaHCO₃ and 100 mL brine andevaporated in vacuo then purified by silica gel flash chromatography onsilica gel (Petroleum ether/ethyl acetate=5:1) to afford SA-L-1 as awhite solid (2.2 g, 24% yield) (eluted first) and SA-L as a white solid(1.1 g, 12% yield) (eluted second).

Synthesis of Compound SA-M.

To a solution of SA-L (2 g, 6.94 mmol) in 50 mL EtOAc, was added Pd\C200 mg. The reaction mixture was hydrogenated in 1 atm H₂ for 15 h. Thereaction mixture was evaporated in vacuo then purified by chromatography(Petroleum ether/ethyl acetate=1:2) to afford SA-M as a white solid (1.5g, 75% yield).

Synthesis of Compound SA-N.

To a solution of SA-M (1 g, 3.4 mmol) in 100 mL MeOH, was added TsOH 50mg, heated to 60° C. for 2 h. The reaction mixture was extracted 500 mLEtOAc, washed with 100 mL sat. NaHCO₃, 100 mL brine solution andevaporated in vacuo to afford SA-N as a white solid (1 g, 91% yield).

Synthesis of Compound SA-O.

To a solution of ethyltriphenylphosphonium bromide (10.67 g, 28.84 mmol)in 30 mL THF, was added KOt-Bu (3.23 g, 28.80 mmol). The reaction washeated to 60° C. for 1 h. SA-N (3.23 g, 9.6 mmol) was added to themixture, stirred at 60° C. for 15 h. The reaction mixture was extracted500 mL EtOAc, washed with brine solutions, and evaporated in vacuoevaporated then purified by chromatography (Petroleum ether/ethylacetate=3:1) to afford SA-O as a white solid (2 g, 62% yield).

Synthesis of Compound SA-P.

To a solution of SA-O (0.5 g, 1.43 mmol) in 10 mL DCM, was added DAST0.5 mL at −78° C. The reaction mixture was stirred at −78° C. for 30min, then was quenched with 5 mL sat. NaHCO₃, extracted with 50 mL DCM,washed with brine, dried and concentrated in vacuo, purified bychromatography (Petroleum ether/ethyl acetate=30:1) to afford SA-P as awhite solid 175 mg, 35% yield.

Synthesis of Compound SA-Q.

To a solution of SA-P (350 mg, 1 mmol) in 20 mL THF, was added 2 M HCl 2mL, stirred at rt for 1 h. The reaction mixture was quenched with 5 mLH₂O and extracted with 100 mL EtOAc, washed with brine and evaporated invacuo then purified by chromatography (petroleum ether/ethylacetate=10:1) to afford SA-Q as a white solid (210 mg, 60% yield).

Synthesis of Compound SA-R.

To a stirred solution of trimethylsulfonium iodide (3.2 g, 16 mmol) in10 mL of DMSO was added NaH (60%; 400 mg, 16 mmol). After stirring atroom temperature for 1 h, a suspension of SA-Q (486 mg, 1.6 mmol) in 5mL of DMSO was added dropwise. After 15 h, the reaction mixture waspoured into ice-cold water (100 mL) and extracted with 300 mL EtOAc,washed with 100 mL brine solution, and evaporated in vacuo then purifiedby chromatography (petroleum ether/ethyl acetate=10:1) to afford SA-Rand its isomer as a white solid (290 mg, 58% yield).

Synthesis of Compound SA-S.

To a solution of SA-R and its isomer (300 mg, 0.94 mmol) in 10 mL THF,was added LiAH₄ (100 mg, 2.7 mmol), stirred at rt for 1 h. The reactionmixture was quenched with 5 mL H₂O and extracted with 100 mL EtOAc,washed with brine and evaporated in vacuo then purified bychromatography (petroleum ether/ethyl acetate=3:1) to afford SA-S as awhite solid (140 mg, 48% yield).

Synthesis of Compound SA-T.

To a solution of SA-S (100 mg, 0.3 mmol) in dry THF (5 mL) was addedborane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF). Afterstirring at room temperature for 1 hour, the reaction mixture was cooledin an ice bath then quenched slowly with 10% aqueous NaOH (1 mL)followed by 30% aqueous solution of H₂O₂ (1 mL). After stirring at roomtemperature for one hour, the mixture was extracted with EtOAc (3×100mL). The combined organic layers were washed with 10% aqueous Na₂S₂O₃(100 mL), brine (100 mL), dried over MgSO₄, filtered and concentrated toafford SA-T as a white solid (100 mg, 91%). The crude product was usedin the next step without further purification.

Synthesis of Compound SA-U.

To a solution of SA-T (100 mg, 0.29 mmol in 20 mL DCM, was added PCC(190 mg, 0.87 mmol), stirred at rt for 2 h. The reaction mixture wasquenched with 5 mL H₂O and extracted with 100 mL EtOAc, washed withbrine and evaporated in vacuo then purified by chromatography (petroleumether/ethyl acetate=3:1) to afford SA-U as a white solid (53 mg, 53%yield).

Synthesis of Compound SA-V.

To a solution of SA-U (40 mg, 0.11 mmol) in MeOH (5 mL) was added 2drops of HBr (48%) followed by bromine (150 mg, 0.33 mmol). Afterstirring at room temperature for 1 h, the reaction mixture was pouredinto ice-water then extracted with EtOAc (10 mL×3). The combined organiclayers were washed with brine (20 mL), dried over MgSO₄, filtered andconcentrated to give crude compound SA-V as a white solid (40 mg, 80%yield). The crude product was used in the next step without furtherpurification.

Example 64. Synthesis of Compound ST-14

To a suspension of ST-13 (20 mg, 0.04 mmol) in THF (5 mL) was addedmorpholine (30 mg, 0.45 mmol) and K₂CO₃ (60 mg, 0.45 mmol). The mixturewas stirred at 25° C. for 15 h. Then the reaction mixture was purifiedwith by reverse-phase prep-HPLC to afford ST-14 as a white solid (9 mg,53% yield).

Example 65. Synthesis of Compound ST-15

To a suspension of ST-13 (20 mg, 0.04 mmol) in THF (5 mL) was added1-(methylsulfonyl)piperazine (74 mg, 0.45 mmol) and K₂CO₃ (60 mg, 0.45mmol). The mixture was stirred at 25° C. for 15 h. Then the reactionmixture was purified with by reverse-phase prep-HPLC to afford ST-15 asa white solid (3 mg, 15% yield).

Example 66. Synthesis of Intermediate SV

Synthesis of Compound SV-1.

To a solution of EtMgBr (5 mmol, 1M in THF) in THF (20 mL) at 0° C. wasadded a solution of compound SA-E (858 mg, 3 mmol) in dry THF (5 mL) viasyringe pump over 30 min. After stirring at 0° C. for 5 h, the reactionmixture was allowed to warm up and stirred at room temperatureovernight. The reaction mixture was quenched with iced-cold water andextracted with EtOAc (15 mL×3). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated. Thewhite residue was purified by flash column chromatography (petroleumether/ethyl acetate=20:1 to 10:1) to give mixture compound (900 mg).

Synthesis of Compound SV-2.

To a solution of compound SV-1 (200 mg, 0.66 mmol) in dry THF (5 mL) wasadded borane-tetrahydrofuran complex (2 mL of 1.0 M solution in THF).After stirring at room temperature for 1 hour, the reaction mixture wascooled in an ice bath then quenched slowly with 10% aqueous NaOH (1 mL)followed by 30% aqueous solution of H₂O₂ (1.2 mL). The mixture wasallowed to stir at room temperature for 1 hour then extracted with EtOAc(3×10 mL). The combined organic layers were washed with 10% aqueousNa₂S₂O₃ (10 mL), brine (10 mL), dried over MgSO₄, filtered andconcentrated to afford compound SV-2 (260 mg, crude). The crude productwas used in the next step without further purification.

Synthesis of Compound SV-3 and SV-4.

To a solution of compound SV-2 (260 mg, crude) was dissolved in 10 mLdichloromethane was added PCC (449 mg,). After stirring at roomtemperature for 24 h, the reaction mixture was extracted withdichloromethane (3×10 mL). The combined organic layers were washed with10% aqueous NaCl (10 mL), brine (10 mL), dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica gel(petroleum ether/ethyl acetate=4:1 to 2:1) to afford title compound SV-3(85 mg), SV-4 (15 mg,) as a white solid.

Synthesis of Compound SV-5.

To a solution of compound SV-3 (30 mg, 0.09 mmol) in MeOH (5 mL) wasadded 2 drops of HBr (48%) followed by bromine (100 mg, 0.62 mmol).After stirring at room temperature for 1 h, the reaction mixture waspoured into ice-water then extracted with ethyl acetate (15 mL×3), Thecombined organic layers were washed with brine (20 mL), dried overMgSO₄, filtered and concentrated to give compound (36 mg crude). Thecrude product was used in the next step without further purification.

Example 67. Synthesis of Compound SV-6

To a suspension of K₂CO₃ (50 mg, 0.36 mmol) in THF (5 mL) was added1-(methylsulfonyl)piperazine (41 mg, 0.3 mmol) and SV-5 (50 mg, 0.122mmol). The mixture was stirred at rt for 15 h. Then the reaction mixturewas poured into 5 mL H₂O and extracted with EtOAc (2×10 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue was purified with byreverse-phase prep-HPLC to afford the title compound as a white solidSV-6 (4 mg, 6.7%). LC-MS: rt=2.36 min, m/z=495.2 (M++1)

Example 68. Synthesis of Compound SV-7

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was addedmorpholine (20 mg, 0.23 mmol) and SV-5 (36 mg, 0.09 mmol). The mixturewas stirred at rt for 15 h. The reaction mixture was poured into 5 mLH₂O and extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue was purified with by reverse-phase prep-HPLC to afford thetitle compound as a white solid (12 mg, 38%). LC-MS: rt=2.46 min,m/z=418.3 (M++1).

Example 69. Synthesis of Intermediate SW

Synthesis of Compound SW-A.

To a solution of reactant SB-F (4.4 g, 15.38 mmol) in dry THF (50 mL)was added ethylmagnesium bromide (3M in THF, 51.28 mL) dropwise at 0° C.The solution was then slowly warmed and stirred at ambient temperaturefor 15 h. Sat. NH₄Cl solution (20 mL) was added to quench the reactionand the resulting solution was extracted with ethyl acetate (3×100 mL).The extracts were washed with brine, dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by flash chromatography (eluant:petroleum ether:ethyl acetate=10:1) to afford product SW-A (3.15 g,10.00 mmol, 64.8%) as a white solid.

Synthesis of Compound SW-B.

To a solution of reactant SW-A (500 mg, 1.58 mmol) in anhydrous THF (10mL) was added BH₃.THF (1.0 M, 7.23 mL, 7.23 mmol) at room temperature,and the solution was stirred at 25° C. overnight. Then the reaction wasquenched by addition of water (5 mL), 2 M NaOH solution (10 mL) wasadded followed by 30% H₂O₂ (10 mL). The resulting mixture was stirred atroom temperature for 1 hour. Then the mixture was diluted with ethylacetate (200 mL) and resulting solution was washed with brine (2×100mL), dried over magnesium sulfate and concentrated in vacuo. The crudeproduct SW-B was used directly in the next step without furtherpurification.

Synthesis of Compound SW-C.

To a solution of reactant SW-B (6.53 g, 19.67 mmol) in anhydrous DCM(100 mL) cooled in an ice-water cooling bath was added pyridiniumchlorochromate (8.48 g, 39.34 mol) in portions. The mixture was stirredat ambient temperature overnight. The solution was then diluted with DCM(50 mL) and filtered. The combined organic solutions were washed withbrine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash chromatography (eluant: petroleum ether:ethylacetate=10:1) to afford product SW-C (2.5 g, 7.53 mmol, yield 39%) as awhite solid.

Synthesis of Compound SW.

To a solution of reactant SW-C (80 mg, 0.24 mmol) in methanol (5 mL) wasadded 48% hydrobromic acid (148 mg, 0.884 mmol) followed by bromine (241mg, 0.077 mL, 1.505 mmol). The solution was heated at 25° C. for 1.5hours, then the mixture was poured into cooled water (50 mL). Theresulting solid was extracted with ethyl acetate (2×50 mL). The combinedorganic extracts were washed with brine (20 mL), dried over magnesiumsulfate and concentrated in vacuo. The crude product SW was useddirectly without further purification in the next step.

Example 70. Synthesis of Compound SW-1

To a solution of crude reactant SW (100 mg, 0.241 mmol) in anhydrous THF(5 mL) was added morpholine (105 mg, 1.2 mmol) followed by potassiumcarbonate (170 g, 1.2 mmol). The solution was heated at 60° C. for 2 hthen the solution cooled to room temperature and diluted with ethylacetate (100 mL). The resulting solution was washed with brine (2×50mL), dried over magnesium sulfate and concentrated in vacuo. The crudeproduct was purified by reverse phase prep-HPLC to afford product SW-1(54 mg, 0.12 mmol, Yield=50%) as a white solid. LCMS: rt=2.42 min,m/z=418 [M+H]

Example 71. Synthesis of Compound SW-2

To a solution of crude reactant SW (100 mg, 0.241 mmol) in anhydrous THF(5 mL) was added 1-methanesulfonyl-piperazine (197 mg, 1.2 mmol)followed by potassium carbonate (170 g, 1.2 mmol). The solution washeated at 60° C. for 2 h. Then the solution was cooled to roomtemperature and diluted with ethyl acetate (100 mL). The resultingsolution was washed with brine (2×50 mL), dried over magnesium sulfateand concentrated in vacuo. The crude product was purified by reversephase prep-HPLC to afford product SW-2 (50 mg, 0.10 mmol, Yield=42%) asa white solid. LCMS: rt=2.42 min, m/z=495 [M+H]⁺

Example 72. Synthesis of Intermediate SX

Synthesis of Compound SX-A-1 and SX-A-2.

To a solution of compound SA-E (800 mg, 2.79 mmol) and PhSO₂CF₂H (540mg, 2.79 mmol) in THF (25 mL) and HMPA (0.5 mL) at −78° C. under N₂ wasadded LHMDS (4 mL, 1M in THF) dropwise. After stirring at −78° C. for 2h, the reaction mixture was quenched with saturated aqueous NH₄Clsolution (10 mL) and allowed to warm to room temperature then extractedwith Et₂O (20 mL×3). The combined organic layers were washed with brine,dried over sodium sulfate, filtered and concentrate. The residue waspurified by silica gel column chromatography (petroleum ether/ethylacetate=10/1) to give the mixture of compound SX-A-1 and SX-A-2 (700mg). The mixture was further purified by chiral-HPLC to afford compoundSX-A-1 (200 mg, t=4.31 min).

Synthesis of Compound SX-B.

To a solution of compound SX-A-2 (100 mg, 0.209 mmol) and anhydrousNa₂HPO₄ (100 mg) in anhydrous methanol (5 mL) at −20° C. under N₂ wasadded Na/Hg amalgam (500 mg). After stirring at −20° C. to 0° C. for 1h, the methanol solution was decanted out and the solid residue waswashed with Et₂O (5×3 mL). The combined organic layers were washed withbrine (20 mL), dried over MgSO₄, filtered and concentrated. The residuewas purified by silica gel chromatography (petroleum ether/ethylacetate=10/1) to give compound SX-B (36 mg, 0.106 mmol, 51%).

Synthesis of Compound SX-C.

To a solution of compound SX-B (150 mg, 0.443 mmol) in dry THF (5 mL)was added borane-tetrahydrofuran complex (1.34 mL of 1.0 M solution inTHF). After stirring at room temperature for 1 hour, the reactionmixture was cooled in an ice bath then quenched slowly with 10% aqueousNaOH (1 mL) followed 30% aqueous solution of H₂O₂ (1.2 mL). The mixturewas allowed to stir at room temperature for 1 hour then extracted withEtOAc (3×10 mL). The combined organic layers were washed with 10%aqueous Na₂S₂O₃ (10 mL), brine (10 mL), dried over MgSO₄, filtered andconcentrated to afford crude compound SX-C (210 mg). The crude productwas used in the next step without further purification.

Synthesis of Compound SX-D.

To a solution of crude compound SX-C (210 mg) was dissolved in 10 mL ofH₂O saturated dichloromethane (dichloromethane had been shaken withseveral milliliters of H₂O then separated from the water layer) wasadded Dess-Martin periodinate (380 mg, 0.896 mmol). After stirring atroom temperature for 24 h, the reaction mixture was extracted withdichloromethane (3×10 mL). The combined organic layers were washed with10% aqueous Na₂S₂O₃ (10 mL), brine (10 mL), dried over MgSO₄, filteredand concentrated. The residue was purified by chromatography on silicagel (petroleum ether/ethyl acetate=5:1) to afford compound SX-D) (90 mg,0.254 mmol, 57%) as a white solid.

Synthesis of Compound SX.

To a solution of compound SX-D (80 mg, 0.226 mmol) in MeOH (5 mL) wasadded 2 drops of HBr (48%) followed by bromine (100 mg, 0.63 mmol).After stirring at room temperature for 1 h, the reaction mixture waspoured into ice-water then extracted with ethyl acetate (15 mL×3), Thecombined organic layers were washed with brine (20 mL), dried overMgSO4, filtered and concentrated to give crude compound SX (95 mg). Thecrude product was used in the next step without further purification.

Example 73. Synthesis of Compounds SX-1 and SX-2

To a suspension of K₂CO₃ (50 mg, 0.36 mmol) in THF (5 mL) was added1-(methylsulfonyl)piperazine (60 mg, 0.36 mmol) and SM SX (100 mg, 0.252mmol). The mixture was stirred at rt for 15 h. The reaction mixture waspoured into 5 mL H₂O and extracted with EtOAc (2×10 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated. The residue was purified with byreverse-phase prep-HPLC to afford the title compound as a white solidSX-1 (8 mg, 6.2%), SX-2 (55 mg, 42.6%). SX-1 LC-MS: rt=2.28 min,m/z=517.3 (M++1); SX-2: LC-MS: rt=2.15 min, m/z=517.3 (M++1)

Example 74. Synthesis of Compound SX-4

To a suspension of K₂CO₃ (25 mg, 0.18 mmol) in THF (5 mL) was addedmorpholine (20 mg, 0.21 mmol) and SX (36 mg, 0.09 mmol). The mixture wasstirred at rt for 15 h. The reaction mixture was poured in to 5 mL H₂Oand extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue mixture was purified with by reverse-phase prep-HPLC toafford SX-3 as a white solid (12 mg, 36%).

Example 77. Synthesis of Intermediate SZ

Synthesis of Compound SB-K.

To a stirred solution of trimethylsulfonium iodide (8.1 g, 36.9 mmol) in100 mL of DMSO was added NaH (60%; 1.26 g, 31.5 mmol). After stirring atroom temperature for 1 h, a suspension of compound SB-F (2.2 g, 7.2mmol) in DMSO (20 mL) was added dropwise. The mixture was stirred foranother 2.5 h, then poured into ice-cold water and extracted with ether(100 mL×3). The combined ether layers were then washed with brine (100mL×3), dried over MgSO₄, filtered, and concentrated to give the crudeproduct SB-K (2.2 g). The crude product was used in the next stepwithout further purification.

Synthesis of Compound SZ-A.

Compound SB-K (2.2 g, 7.3 mmol) was dissolved in dry ethanol (250 mL),and Na (672 mg, 29.2 mmol) was added. The solution was stirred refluxfor 6 h. Ethanol was evaporated off and the residue was dissolved indichloromethane and washed with H₂O (3×50 mL) and brine (100 mL), driedover MgSO₄, filtered, and concentrated. The crude target compound waspurified by via silica gel chromatography (petroleum ether/ethylacetate=10:1 to 5:1), and concentrated to give SZ-A (1.8 g, 82%) as awhite solid.

Synthesis of Compound SZ-B.

To a solution of compound SZ-A (1.8 g, 5.2 mmol) in dry THF (50 mL) wasadded borane-tetrahydrofuran complex (20 mL of 1.0 M solution in THF).After stirring at room temperature for 1 hour, the reaction mixture wascooled in an ice bath then quenched slowly with 10% aqueous NaOH (10 mL)followed 30% aqueous solution of H₂O₂ (12 mL). The mixture was allowedto stir at room temperature for 1 hour then extracted with EtOAc (3×100mL). The combined organic layers were washed with 10% aqueous Na₂S₂O₃(100 mL), brine (100 mL), dried over MgSO₄, filtered and concentrated toafford crude compound SZ-B (1.8 g, 100%). The crude product was used inthe next step without further purification.

Synthesis of SZ-C.

To a solution of crude compound SZ-B (1.8 g, 5.2 mmol) was dissolved in60 mL of H₂O saturated dichloromethane (dichloromethane had been shakenwith several milliliters of H₂O then separated from the water layer) wasadded Dess-Martin periodinate (4.4 g, 10.4 mmol). After stirring at roomtemperature for 24 h, the reaction mixture was extracted withdichloromethane (3×100 mL). The combined organic layers were washed with10% aqueous Na₂S₂O₃ (100 mL), brine (100 mL), dried over MgSO₄, filteredand concentrated. The residue was purified by chromatography on silicagel (petroleum ether/ethyl acetate=10:1 to 5:1) to afford SZ-C (1 g, 2.8mmol, 56% for two steps) as a white solid. LCMS: Rt=7.25 min. m/z=345.1[M-17]⁺.

Synthesis of Intermediate SZ.

To a solution of compound SZ-C (600 mg, 1.65 mmol) in MeOH (20 mL) wasadded 5 drops of HBr (48%) followed by bromine (264 mg, 1.65 mmol).After stirring at room temperature for 1 h, the reaction mixture waspoured into ice-water then extracted with ethyl acetate (100 mL×3). Thecombined organic layers were washed with brine (200 mL), dried overMgSO₄, filtered and concentrated to give crude compound SZ (600 mg,100%). The crude product was used in the next step without furtherpurification. LCMS: Rt=7.25 min. m/z=463.1 [M+Na]⁺.

Example 78. Synthesis of Compound SZ-1

To a suspension of K₂CO₃ (26 mg, 0.22 mmol) in THF (5 mL) was added1-(methylsulfonyl) piperazine (36 mg, 0.22 mmol) and compound SZ (50 mg,0.11 mmol). After stirring at room temperature for 15 h, the reactionmixture was poured into 5 mL H₂O and extracted with EtOAc (2×10 mL). Thecombined organic layers were washed with brine (2×10 mL), dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by reverse-phase prep-HPLC to afford SZ-1 as a white solid (20mg, 33%). LCMS: Rt=2.29 min. m/z=525.1 [M+H]⁺.

Example 79. Synthesis of Compound SZ-2

To a suspension of K₂CO₃ (19 mg, 0.14 mmol) in THF (5 mL) was addedmorpholine (12 mg, 0.14 mmol) and compound SZ (30 mg, 0.07 mmol). Afterstirring at room temperature for 15 h, the reaction mixture was pouredinto 5 mL H₂O and extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine (2×10 mL), dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified byreverse-phase prep-HPLC to afford SZ-2 as a white solid (14.4 mg, 0.032mmol, 46.0%). LCMS: Rt=2.36 min. m/z=448.4 [M+H]⁺.

Assay Methods

Compounds provided herein can be evaluated using various in vitro and invivo assays; examples of which are described below.

Steroid Inhibition of TBPS Binding

[35S]-t-Butylbicyclophosphorothionate (TBPS) binding assays using ratbrain cortical membranes in the presence of 5 μM GABA has been described(Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson etal, Mol. Pharmacol. 1994, 46, 977-985; Lewin, A. H et al., Mol.Pharmacol. 1989, 35, 189-194).

Briefly, cortices are rapidly removed following decapitation of carbondioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices arehomogenized in 10 volumes of ice-cold 0.32 M sucrose using aglass/teflon homogenizer and centrifuged at 1500×g for 10 min at 4° C.The resultant supernatants are centrifuged at 10,000×g for 20 min at 4°C. to obtain the P2 pellets. The P2 pellets are resuspended in 200 mMNaCl/50 mM Na—K phosphate pH 7.4 buffer and centrifuged at 10,000×g for10 min at 4° C. This washing procedure is repeated twice and the pelletsare resuspended in 10 volumes of buffer. Aliquots (100 μL) of themembrane suspensions are incubated with 3 nM [³⁵S]-TBPS and 5 μLaliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final0.5%) in the presence of 5 μM GABA. The incubation is brought to a finalvolume of 1.0 mL with buffer. Nonspecific binding is determined in thepresence of 2 μM unlabeled TBPS and ranged from 15 to 25%. Following a90 min incubation at room temp, the assays are terminated by filtrationthrough glass fiber filters (Schleicher and Schuell No. 32) using a cellharvester (Brandel) and rinsed three times with ice-cold buffer. Filterbound radioactivity is measured by liquid scintillation spectrometry.Non-linear curve fitting of the overall data for each drug averaged foreach concentration is done using Prism (GraphPad). The data are fit to apartial instead of a full inhibition model if the sum of squares issignificantly lower by F-test. Similarly, the data are fit to a twocomponent instead of a one component inhibition model if the sum ofsquares is significantly lower by F-test. The concentration of testcompound producing 50% inhibition (IC₅₀) of specific binding and themaximal extent of inhibition (I_(max)) are determined for the individualexperiments with the same model used for the overall data and then themeans±SEM.s of the individual experiments are calculated. Picrotoxinserves as the positive control for these studies as it has beendemonstrated to robustly inhibit TBPS binding.

Various compounds are or can be screened to determine their potential asmodulators of [³⁵S]-TBPS binding in vitro. These assays are or can beperformed in accordance with the above discussed procedures. The TBPSbinding evaluation of the exemplary compounds are shown in Table 1.

Patch Clamp Electrophysiology of Recombinant α₁β₂γ₂ and α₄β3δ GABA_(A)Receptors

Cellular electrophysiology is used to measure the pharmacologicalproperties of our GABA_(A) receptor modulators in heterologous cellsystems. Each compound is tested for its ability to affect GABA mediatedcurrents at a submaximal agonist dose (GABA EC₂₀=2 μM). LTK cells arestably transfected with the α₁β₂γ₂ subunits of the GABA receptor and CHOcells are transiently transfected with the α₄β3δ subunits via theLipofecatamine method. Cells were passaged at a confluence of about50-80% and then seeded onto 35 mm sterile culture dishes containing 2 mlculture complete medium without antibiotics or antimycotics. Confluentclusters of cells are electrically coupled (Pritchett et al., Science,1988, 342, 1306-1308.). Because responses in distant cells are notadequately voltage clamped and because of uncertainties about the extentof coupling (Verdoorn et al., Neuron, 1990, 4, 919-928), cells werecultivated at a density that enables the recording of single cells(without visible connections to other cells).

Whole cell currents were measured with HEKA EPC-10 amplifiers usingPatchMaster software or by using the high throughput QPatch platform(Sophion). Bath solution for all experiments contained (in mM): NaCl 137mM, KCl 4 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, HEPES 10 mM, D-Glucose 10 mM, pH(NaOH) 7.4. In some cases 0.005% cremophor was also added. Intracellular(pipette) solution contained: KCl 130 mM, MgCl₂ 1 mM, Mg-ATP 5 mM, HEPES10 mM, EGTA 5 mM, pH 7.2. During experiments, cells and solutions weremaintained at room temperature (19° C.-30° C.). For manual patch clamprecordings, cell culture dishes were placed on the dish holder of themicroscope and continuously perfused (1 ml/min) with bath solution.After formation of a Gigaohm seal between the patch electrodes and thecell (pipette resistance range: 2.5 MΩ-6.0 MΩ; seal resistance range: >1GΩ) the cell membrane across the pipette tip was ruptured to assureelectrical access to the cell interior (whole-cell patch-configuration).For experiments using the QPatch system, cells were transferred assuspension to the QPatch system in the bath solution and automated wholecell recordings were performed.

Cells were voltage clamped at a holding potential of −80 mV. For theanalysis of test articles, GABA receptors were stimulated by 2 μM GABAafter sequential pre-incubation of increasing concentrations of the testarticle. Pre-incubation duration was 30 s and the duration of the GABAstimulus was 2 s. Test articles were dissolved in DMSO to form stocksolutions (10 mM). Test articles were diluted to 0.01, 0.1, 1, and 10 μMin bath solution. All concentrations of test articles were tested oneach cell. The relative percentage potentiation was defined as the peakamplitude in response to GABA EC₂₀ in the presence of the test articledivided by the peak amplitude in response to GABA EC₂₀ alone, multipliedby 100.

TABLE 1 TBPS binding evaluation of the exemplary compounds TBPS IC50Entry Structure (nM)  1.

D  2.

E  3.

E  4.

D  5.

E  6.

D  7.

B  8.

D  9.

E 10.

C 11.

D 12.

E 13.

D 15.

E 17.

E 18.

D 19.

E 20.

D 21.

D 22.

D 23.

E 24.

E 25.

C 26.

E 27.

D 28.

E 31.

B 32.

E 33.

D 34.

E 35.

E 36.

D 37.

D 38.

E 39.

D 40.

E 41.

E 42.

E 43.

E 44.

E 45.

E 46.

E 47.

E 48.

E 49.

E 50.

E 51.

D 52.

D 53.

D

For Table 1, “A” indicates an IC50<10 nM, “B” indicates an IC50 of 10 nMto 50 nM, “C” indicates an IC50 of ≥50 nM to 100 nM, “D” indicates anIC50 of ≥100 nM to 500 nM, and “E” indicates IC50≥500 nM.

The biochemical evaluation of the exemplary compounds over GABA alpha-1are shown in Table 2.

TABLE 2 Electrophysiological evaluation of the exemplary compounds atGABA_(A)-R. GABAa GABAa alpha1 alpha1 (α1β2γ2) (α1β2γ2) En- EC₅₀ Emaxtry Structure (nM) (%) 1

D B 2

D A 3

E A

For Table 2, column “GABAa alpha1 (α1β2γ2)EC₅₀ (nM)”: “A” indicates anEC50<100 nM, “B” indicates an EC50 of ≥100 nM to 500 nM, “C” indicatesan EC50 of ≥500 nM to 1000 nM, “D” indicates an EC50 of ≥1000 nM to 2000nM, and “E” indicates EC50≥2000 nM. Column “GABAa alpha1 (α1β2γ2)Emax(%)”:“a” indicates Emax of 0-500%; “B” indicates Emax of >500-1000%; “c”indicates Emax of >1000%.

TABLE 3 Electrophysiological evaluation of the exemplary compounds atGABA_(A)-R. GABA (α1β2γ2) GABA (α4β3δ) En- Qpatch in Ltk, Qpatch in CHO,try Compound % efficacy at 10 μM % efficacy at 10 μM  4.

B D  6.

B D  7.

B D  8.

C C  9.

B D 10 

B D 17 

B D 19 

C D 26 

B D 27 

B B 28 

B D 29 

B D 30 

C D 32 

C D 34 

B D 35 

B D 36 

B D 45 

A C 47 

A D 50 

A D 55 

A D 56 

B D 57.

C D 58.

C D

For Table 3. GABAA receptors α1β2γ2 and α4β3δ% efficacy: “A” 10-100, “B”≥100-500, “C” ≥500; D indicates the data is not available or has notbeen determined.

OTHER EMBODIMENTS

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A method for treating a CNS-related disorder in a human subject inneed thereof, comprising administering to the human subject atherapeutically effective amount of (a) a compound of Formula (I) or apharmaceutically acceptable salt thereof or (b) a pharmaceuticalcomposition comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier:

wherein:

represents a single or double bond; R¹ is substituted or unsubstitutedC₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, or substituted or unsubstituted C₃₋₆carbocyclyl; R² is hydrogen, halogen, substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, or substituted or unsubstituted C₃₋₆carbocyclyl, or —OR^(A2), wherein R^(A2) is hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, or substituted orunsubstituted C₃₋₆ carbocyclyl; R^(3a) is hydrogen or —OR^(A3), whereinR^(A3) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl, and R^(3b) ishydrogen; or R^(3a) and R^(3b) are joined to form an oxo (═O) group;each instance of R^(4a) and R^(4b) is independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl, alkoxy, halogen, or —OR^(A4),wherein R^(A4) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, or substituted or unsubstituted C₃₋₆ carbocyclyl, providedif the

between C5 and C6 is a single bond, then the hydrogen at C5 is in thealpha or beta configuration; and provided if the

between C5 and C6 is a double bond, R^(4b) is absent; A is one of thefollowing formulae:

each instance of R⁵ is, independently, halogen, —NO₂, —CN, —OR^(GA),—N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA),—C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂,—N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, or —N(R^(GA))S(═O)₂R^(GA); substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₄ carbocylyl, substituted or unsubstituted 3- to 4-memberedheterocylyl, or optionally two R^(GA) are taken with the interveningatoms to form a substituted or unsubstituted 3- to 4-memberedcarbocyclic or heterocyclic ring; each instance of R^(AN) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl,—C(═O)R^(GA), —C(═O)OR^(GA), —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —S(═O)₂N(R^(GA))₂, —S(O)R^(GA), e.g., —S(═O)R^(GA),—S(═O)OR^(GA), —S(═O)N(R^(GA))₂, or a nitrogen protecting group; eachinstance of R^(GA) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocylyl, substituted or unsubstituted 3- to 6-memberedheterocylyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, or twoR^(GA) groups are taken with the intervening atoms to form a substitutedor unsubstituted carbocyclic or heterocyclic ring; p is 1 or 2; and e is0, 1, 2, 3, 4, or 5; provided that when A is (A-3), or (A-5), e is 1, 2,3, 4, or
 5. 2. The method of claim 1, wherein the compound is of Formula(II):

or a pharmaceutically acceptable salt thereof.
 3. (canceled)
 4. A methodfor treating a CNS-related disorder in a human subject in need thereofcomprising administering to the human subject a therapeuticallyeffective amount of (a) a compound of Formula (IV) or a pharmaceuticallyacceptable salt thereof or (b) a pharmaceutical composition comprising acompound of Formula (IV) or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier, wherein the compound offormula (IV) is:


5. The method of claim 1, wherein the compound is of Formula (V):

or a pharmaceutically acceptable salt thereof.
 6. The method of claim 5,wherein R^(AN) is substituted or unsubstituted hydrogen, substituted orunsubstituted C₁₋₆ alkyl, —C(═O)R^(GA), —C(═O)OR^(GA), —C(═O)N(R^(GA))₂,or —S(═O)₂R^(GA).
 7. The method of claim 1, wherein the compound is ofFormula (VI):

or a pharmaceutically acceptable salt thereof.
 8. The method of claim 7,wherein the compound is of Formula (VI-a):


9. The method of claim 1, wherein e is
 1. 10. The method of claim 1,wherein R₅ is substituted or unsubstituted C₁₋₆ alkyl.
 11. The method ofclaim 1, wherein R₅ is —CH₃.
 12. The method of claim 1, wherein R₅ isOR^(GA) wherein R^(GA) is hydrogen or substituted or unsubstituted C₁₋₆alkyl.
 13. The method of claim 1, wherein R₅ is OH.
 14. The method ofclaim 1, wherein R₅ is —S(═O)₂R^(GA) wherein R^(GA) is substituted orunsubstituted C₁₋₆ alkyl.
 15. The method of claim 1, wherein R₅ is—S(═O)₂CH₃.
 16. The method of claim 1, wherein R₅ is —C(═O) R^(GA)wherein R^(GA) is substituted or unsubstituted C₁₋₆ alkyl.
 17. Themethod of claim 1, wherein R₅ is —C(═O)CH₃.
 18. The method of claim 1,wherein R₅ is —C(═O)N(R^(GA))₂ wherein R^(GA) is hydrogen or substitutedor unsubstituted C₁₋₆ alkyl.
 19. The method of claim 1, wherein R₅ is—C(═O)NHCH₃.
 20. The method of claim 1, wherein

between C5 and C6 is a double bond and R^(4b) is absent.
 21. The methodof claim 1, wherein

between C5 and C6 is a single bond.
 22. The method of claim 1, whereinthe compound is selected from the group consisting of:


23. (canceled)
 24. (canceled)
 25. The method of claim 1, wherein theCNS-related disorder is a sleep disorder, a mood disorder, aschizophrenia spectrum disorder, a convulsive disorder, a disorder ofmemory and/or cognition, a movement disorder, a personality disorder,autism spectrum disorder, pain, traumatic brain injury, a vasculardisease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus.
 26. The method of claim 1, wherein thecompound is administered orally, subcutaneously, intravenously, orintramuscularly.
 27. The method of claim 1, wherein the compound isadministered chronically.
 28. The method of claim 25, wherein the CNSdisorder is mood disorder.
 29. The method of claim 28, wherein the mooddisorder is depression.
 30. The method of claim 29, wherein thedepression is postnatal depression.